PHS 208 Material PDF

Nervous system is a system of:  communication that allows the individual to interact with his external environment.  integration that coordinates functions of various internal organ systems of the body. Neural connections between body parts provide the basis for anatomical and physiological communications that help in smooth execution of most of the systemic functions such as gastrointestinal functions, secretion of hormones, functions of heart, lungs and kidney, and musculoskeletal system and so on. Division of Nervous System  Central Nervous System  Peripheral Nervous System  Autonomic Nervous System Central Nervous System The central nervous system (CNS) includes:  Brain  Spinal cord. Brain is situated in the skull, which continues into the vertebral canal as the spinal cord. Brain Brain is divided into three parts: 1. Prosencephalon (forebrain): subdivided into  Telencephalon: this include cerebral hemisphere, amygdala, basal ganglia, hippocampus Functions: The telencephalon is meant for perception of sensations, cognition, learning and memory, and planning and programming of responses.  Diencephalon: this include thalamus, hypothalamus, subthalamus and metathalamus Function: The diencephalon is primarily meant for relay of information to cortex, and control of autonomic and endocrine functions. 2. Mesencephalon (midbrain) This includes corpora quadrigemina, cerebral peduncles, substantia nigra, tegmentum and many midbrain nuclei. Function: Midbrain contains central pattern generator for locomotion and nuclei for righting reflexes. It also contains a part of reticular formation. 3. Rhombencephalon (hindbrain): subdivided into  Metencephalon: this includes pons and cerebellum  Myelencephalon: this includes medulla oblongata. The midbrain, pons, and medulla are together known as brainstem. The main functions of brainstem are control of cardiovascular and respiratory functions, motor activities, sleep-wakefulness and visceral functions. Spinal Cord Spinal cord starts from the base of the skull as the extension of medulla and continues till the body of first lumbar vertebra. Thus, spinal cord does not run the full length of the vertebral column in adults. 1. The space at the end of spinal cord, especially between L1 and L2 vertebral segments is used in tapping cerebrospinal fluid during lumbar puncture. 2. Spinal cord has 31 segments, each having a motor and a sensory nerve root. The nerve roots combine to form the 31 bilaterally symmetrical pairs of spinal nerves. 3. Spinal cord contains all the ascending and descending tracts. 4. The main function of spinal cord is to receive sensory inputs from peripheral structures via somatic nerves and transmit them to the brain and convey the signals originating from brain motor and autonomic areas to the target structures. Cellular Component of Central Nervous System Despite its complexity, CNS consists of only two principal cell types: 1. Glial cells: it is also called neuroglia. Neuroglias support and protect the neurons and maintain homeostasis of fluids that bath the neurons 2. Neurons. Neurons transmit impulses in the form of action potentials. Neuroglias are 10– 30 times plentiful than neurons. Glial cells Glial cells neither conduct action potential nor form functional synapse with other cells. However, they can be passively polarized in response to nearby neural activity. Though glial cells generally provide support for neurons, their functions are complex and not completely understood. Glial cells can multiple Functions of Glial Cells  They form the mechanical matrix in which neurons are embedded.  They play metabolic and nutritive roles for neurons.  They may help to regulate blood flow through the brain.  They may act as a sink or source of ions.  They insulate axons and synapses and electrically isolate them from one another.  They phagocytose neural debris. Types of Glial Cells in CNS  Astrocytes (astroglia)  Oligodendrocytes (oligodendroglia)  Ependymal cells  Microglia. Astrocytes Astrocytes are so named because of their star shape. They are found abundantly throughout the brain and spinal cord. Processes of astrocytes surround the neurons and their axons and often terminate on the wall of blood vessels. Functions of astrocytes are as follows: 1. They provide the mechanical matrix. 2. They serve metabolic and nutritive functions for neurons. 3. Synapses in CNS are usually surrounded by the processes of astrocytes. Thus, astrocytes electrically insulate synapses and separate them from one another. Oligodendrocytes Oligodendrocytes are found close to the myelinated axons in the brain and spinal cord.  The processes of oligodendrocytes wrap many times around an axon to form the myelin sheath. This sheath not only insulates axons from one another, but also limits current flow across the axon membrane (axolemma).  Because of this myelination, action potential is conducted in a saltatory fashion in myelinated fibers, which is much faster than the transmission of impulse in unmyelinated fibers.  Oligodendrocytes provide myelin sheath for neurons in CNS in a much similar way the Schwann cells do for peripheral nerves. Microglia Microglia are the smallest cells in the central nervous system. They are the scavenger cells in brain. If the nervous tissue is damaged or infected, these cells enlarge and become mononuclear phagocytes to eliminate debris and organisms. Ependymal Cells Ependymal cells line the surfaces of the brain’s ventricles and central canal of the spinal cord. Their function is unclear. Neuron The neuron is a nerve cell. It is the functional unit of the nervous system. Structure of Neuron A neuron consists of:  Cell body (soma)  Dendrites  Axon Soma The soma or the cell body consists of nucleus and cytoplasm. Cytoplasm contains many organelles like endoplasmic reticulum, a prominent Golgi apparatus, many mitochondria and cytoskeletal elements that include microfilaments (neurofilaments) and microtubules. The special granules present in the cytoplasm are Nissl bodies that are modified rough endoplasmic reticulum and act as biosynthetic apparatus for synthesis of proteins in the neurons. The Nissl bodies are present throughout the soma except in the axon hillock. Nucleus is centrally or eccentrically placed and contains a nucleolus. Dendrites These are tapering processes of variable complexity that arise from the soma. They account for more than 90% of the total surface area of the neuron. The parts of dendrites that are close to the cell body (proximal dendrites) contain Nissl granules and Golgi apparatus, whereas the parts that are present away from the soma (distal dendrites) contains no Nissl granules. The dendrites contain mainly the microfilaments and microtubules. Dendrites and cell bodies are the main parts of the neuron for receiving information and therefore form the receiving or receptor zone of the neuron. Dendrites conduct impulses toward the cell body. Axon The axon is the longest process of the neuron. It arises from the soma at a specialized region called axon hillock. The axon hillock is the tapered part of the cell body that gives rise to axon. The differences between the axon hillock (proximal part of the axon) and the proximal dendrites (proximal part of the dendrites) are that the axon hillock does not contain Nissl granules, endoplasmic reticulum and Golgi apparatus, whereas the proximal dendrites contain all these cell organelles. The axon hillock continues as unmyelinated proximal part of the axon called as the initial segment. The initial segment is the spike initiation zone of the neuron as action potential normally arises here due to summation of electrical activities that have occurred in the cell body and dendrites. The interior of the axon is called as axon cylinder that contains axoplasm. The axoplasm contains mitochondria, neurofibrils and the vesicles. Nissl bodies are not found in the axon. The neurotransmitter substances are synthesized in the soma and transported in the axoplasm by means of axonal flow to the synapse. If axons are covered by myelin sheath, the nerve fibers are known as myelinated fibers and without the cover, they are unmyelinated fibers. Types of Neuron  Unipolar neurons: have a single process, they are usually found in invertebrate. In vertebrate, they are found in ANS  Pseudounipolar neurons: In pseudounipolar neurons, axon after originating from soma splits into central and peripheral processes. The example is dorsal root ganglion cell (primary sensory neurons with cell bodies in dorsal root ganglion).  Bipolar neurons: In these neurons, two processes arise from the cell body. The example is the bipolar cell of retina.  Multipolar neurons: In multipolar neurons, many processes arise from the soma. The example is a spinal motor neuron.  Golgi type 1: These are the neurons with short axons. Dendrites of these neurons terminate near the soma. The example is cortical inhibitory neurons.  Golgi type 2: Axons of Golgi type 2 neurons are long. Cortical motor neurons (neurons that give rise to corticospinal tract) are the examples.  Sensory neurons: These are the neurons that carry impulses from the receptors to the central nervous systems. These are called afferent neurons (afferent fibers).  Motor neurons: These are the neurons that carry impulses from the central nervous system to the target organs. These are called efferent neurons (efferent fibers).  Pyramidal cells: Dendrites of these cells spread like pyramids. The example is hippocampal pyramidal neurons.  Stellate cells: Radial shaped spread of dendrites occurs in these cells. The examples are cortical stellate cells. Synapses in CNS Communication, the major function of the nervous system, is achieved through synaptic transmission, the transmission of impulses through synapses. Synapses are the neuro-neuronal junctions through which information from one neuron passes to the other. Through the synapses, neuronal messages are conveyed to the appropriate target structures in the CNS. Command signals from CNS to the peripheral organs are also conveyed through the synapses. The higher functions of CNS (e.g. processing and integration of information, learning, memory, etc.) are also possible because of activation and alteration of activities at synapses. Formation of new synapses and synaptic modifications continue throughout the life of an individual. Types of Synapse  Based on the parts of the neurons involved in the formation of synapse, four types of synapses are found in CNS: 1. Axodendritic Synapse: In this type of synapse, axon of presynaptic neuron connects with dendrite of postsynaptic neuron. This is the commonest synapse in CNS. The axon terminal may synapse with the spinous process of the dendrite (axospinous synapse) or with the shaft of the dendrite (shaft synapse) 2. Axosomatic Synapse: In this variety, axon of presynaptic neuron synapses with cell body of postsynaptic neuron. This is also a common form of synapse in CNS. 3. Axoaxonic Synapse: In axoaxonic type, axon of presynaptic neuron synapses with axon of postsynaptic neuron 4. Dendrodendritic Synapse: In this type, dendrite of presynaptic neuron connects to the dendrite of postsynaptic neuron. In CNS, axodendritic synapse is the common type of synapse followed by axosomatic synapse. For example, in cerebral cortex, about 80% of neurons synapse on dendrites, whereas only 15% end on cell bodies. Axoaxonic synapse is less common and dendrodendritic synapse is the rare one. The ratio of synapses to neuron in human forebrain is about 40000 : 1.  Synapses are of three types according to the mode of transmission of the impulse. 1. Chemical synapse: Transmission of the impulse occurs through release of neurotransmitters. 2. Electrical synapse: Transmission of the impulse occurs through gap junctions. 3. Conjoint synapse: Partly electrical and partly chemical  According to the number of neurons involved 1. “one to one” synapse eg neuromuscular junction 2. “many to one” synapse: “many to one” is the usual type found in CNS 3. “one to many” synapse: “one to many” is less frequent. In ANS, usually ‘one to one’ synapse is found in parasympathetic and ‘one to many’ type is found in sympathetic system. Mechanism of Synaptic Transmission According to the nature of transmission, synapses are categorized into chemical and electrical synapse. As chemical synapses are very common, and electrical synapses are sparse in CNS Functional anatomy of Synapse The neuron from which the information passes through the synapse is the presynaptic neuron and the neuron, which receives the information, is the postsynaptic neuron. The part of the presynaptic axon terminal forming the synapse is called presynaptic membrane and that of the postsynaptic neuron is called the postsynaptic membrane. The space between presynaptic and postsynaptic membrane is called the synaptic cleft. The presynaptic axon terminal, postsynaptic membrane and the synaptic cleft form the synapse Presynaptic Axon Terminal The presynaptic membrane is the part of an axon terminal of the presynaptic neuron. The terminal of presynaptic neuron typically ends in small bulbous enlargement called terminal bouton or synaptic knob, which is about 1 mm in diameter. Synaptic bouton contains two specialized structures: 1. Numerous synaptic vesicles that contain neurotransmitters. 2. Dense tufts or projections that are made up of filamentous proteins, which contact larger filaments in the axoplasm. Synaptic Vesicles There are three types of synaptic vesicles: 1. Small vesicles with clear-core: Small-clear vesicles contain acetylcholine, GABA, glycine or glutamate. 2. Small vesicle with dense-core: Small-dense vesicles contain catecholamines 3. Large vesicle with dense-core: large-dense vesicles contain neuropeptide.  Large vesicles are present throughout the presynaptic terminals and are released by exocytosis from all parts of the presynaptic membrane.  The small vesicles are located close to the presynaptic membrane and are released to the synaptic cleft through the active zone by exocytosis. The small vesicles after discharging their content are recycled back into the terminal. The vesicles are endocytosed and then fused with the endosomes. New vesicles that are formed from endosomes by budding are refilled with the transmitter chemicals. Vesicles then move close to the active zone and undergo docking and priming before discharging their content into the synaptic cleft. Dense Tufts These are filamentous projections present in close contact with vesicles and play an important role in exocytosis of vesicles. Dense tufts are present mainly in active zone Active Zone Presynaptic terminal also contains few large mitochondria. A region of presynaptic membrane is modified to form active zone, which contains many proteins and calcium channels. Release of vesicles containing neurotransmitters occurs mainly through the active zone Synaptic Cleft The synaptic cleft is the gap between pre- and post-synaptic membranes, which is about 20 to 50 nm wide. This space is filled with extracellular fluid. Transmitter molecules released from the presynaptic terminal diffuse across the cleft to reach the postsynaptic receptors. Postsynaptic Membrane The postsynaptic membrane usually is a part of a dendritic spine, but may be a part of a cell body (soma) or part of an axon, which contains receptors for the neurotransmitters. 1. The area of the postsynaptic membrane modified for synaptic transmission is called postsynaptic density. 2. Postsynaptic density is the cluster of receptors for transmitter embedded within the postsynaptic membrane. Neurotransmitter is the chemical substance used for transfer of information through the synapse. The neurotransmitter amplifies the effect of the action potential arriving at the synapse. Due to this amplification, presynaptic action potential after passing through the synaptic cleft stimulates the postsynaptic neuron. The arrangement in the synapse is such that the neurotransmitter released from presynaptic nerve ending acts on a wide area of the postsynaptic membrane and activates a large number of receptors (ion channels) to activate postsynaptic potential Steps of Synaptic Transmission Synaptic transmission is the process by which information from presynaptic neuron passes to the postsynaptic neuron through the synapse. In a chemical synapse, it occurs due to release of neurotransmitter from presynaptic nerve terminal that initiates action potential in the postsynaptic neuron. The mechanism of synaptic transmission can be divided into presynaptic and postsynaptic mechanisms. Presynaptic Mechanisms Five major steps are involved in the presynaptic mechanism of synaptic transmission. 1. Vesicles containing neurotransmitter molecules that are concentrated at active zone of the presynaptic axon terminal undergo docking and priming. Docking is the process by which vesicles attach with the membrane and priming is the process by which the vesicles become ready to discharge their content in response to a stimulus. 2. The action potential that arrives at presynaptic axon terminal depolarizes the presynaptic membrane. 3. Depolarization of membrane causes opening of voltage-gated calcium channels that allows calcium to enter the axon terminal through the active zone. 4. Increase in calcium concentration in the presynaptic terminal increases calcium-mediated exocytosis of the vesicles. Calcium causes fusion of vesicles to the presynaptic membrane by causing contraction of microfilaments in the dense tuft that facilitates their movement, and then help to discharge their content into the cleft. Kiss and Run Discharge: Discharge of synaptic vesicular contents takes place through a small hole in the cell membrane, which immediately closes rapidly. − In this process, the main vesicle remains inside the cell. This is called kiss-and-run discharge. − Following discharge, some vesicles are quickly recovered by endocytosis and refilled locally, in which the endocytic process is short- circuited. 5. Transmitter is released into the synaptic cleft in a quantized amount that diffuses passively across the cleft to the postsynaptic membrane. Quantal release of neurotransmitter is sometimes called Dale’s phenomenon. From the calcium influx to the transmitter release takes about 200 μs. Role of Membrane Proteins Normally, small synaptic vesicles recycle in the presynaptic nerve terminal. The mature vesicles move to the active zone, dock and get primed. When action potential arrives, calcium influx facilitates fusion of vesicles with presynaptic membrane that causes discharge of granular content into the synaptic cleft. 1. Vesicle membrane then gets coated with clathrin and taken up by endocytosis into the presynaptic terminal where it is reutilized for neurotransmitter packaging. 2. Fusion of synaptic vesicle with cell membrane is facilitated by synaptobrevin, a v-snare protein present in vesicular membrane, and syntaxin, a t-snare protein present in the cell membrane. 3. In fact, synaptobrevin attaches and interacts with syntaxin for docking and priming of vesicles. 4. Various other synaptic proteins (SNAP 25 connected with syntaxin, and α/γ SNAPs connected with synaptobrevin) facilitate the interaction between synaptobrevin and syntaxin. 5. A multi-protein complex regulated by small GTPase like rab3 also participates in the process. Postsynaptic Mechanisms The following events take place in postsynaptic cell. 1. Neurotransmitter binds with the receptors in the postsynaptic membrane and brings about conformational change in the receptor that either opens an ion channel or triggers a cascade of biochemical reactions that generate a second messenger, which in turn generates change in ionic permeability of the cell. 2. Some of the transmitter molecules diffuse away from the postsynaptic receptor that are cleared either by enzymatic degradation or taken back into the presynaptic After the binding of the neurotransmitter with receptors, the ion channels in the postsynaptic membrane open up and movement of ions occurs. Depending on the ion (cation or anion) and the direction of their movement, the membrane potential of the postsynaptic membrane changes either towards depolarization or hyperpolarization. This change in membrane potential, also called synaptic potential, creates signal in the postsynaptic neuron. Synaptic Potential Synaptic potential is of longer duration than an action potential. When it is excitatory, it can cause repeated firing of initial segment of the postsynaptic neuron. Types of Synaptic potentials 1. Excitatory Postsynaptic Potential If the potential changes in the postsynaptic membrane during synaptic transmission is towards depolarization, the potential is called EPSP. For example, if initially the RMP was –70 mV, which becomes –60 mV during synaptic transmission, then it is EPSP. 1. The latency of EPSP is about 0.5 ms. EPSP reaches its peak at 11.5 ms after the entry of afferent impulses into the spinal cord, which then declines exponentially. A single EPSP leads to a change of 0.5–2 mV only. Though the EPSP produced at one synaptic knob is small, EPSP at many synaptic knobs summate. 2. EPSP of optimum magnitude leads to excitation of the postsynaptic neuron. 3. During this potential, excitability of postsynaptic neuron increases to other stimuli, and therefore, the potential is called excitatory postsynaptic potential. 4. EPSPs are produced by transmitters like acetylcholine, nor-adrenaline etc. Ionic Basis EPSP is caused by opening of Na+ or Ca2+ ion channels in the postsynaptic membrane that results in influx of Na+ or Ca2+ and causes depolarization. EPSP is also caused by closure of K+ ion channels. Slow EPSP Slow EPSP has been observed in autonomic ganglia and cortical neurons. They have the latency of 100–500 ms, and they persist for several seconds. They are usually due to decreased K+ conductance. 2. Inhibitory Postsynaptic Potential During synaptic transmission, if the potential of the postsynaptic membrane is carried towards hyperpolarization, then the potential is called IPSP. This is because the hyperpolarization leads to inhibition of the postsynaptic neuron. For example, if the RMP was –70 mV, and after transmission it becomes –80 mV, then the potential is IPSP, which is of –10 mV. 2. Actually, a very small change occurs due to an IPSP, i.e. about 0.5 mV. During this potential, excitability of postsynaptic neuron decreases to other stimuli, and therefore, the potential is called inhibitory postsynaptic potential. 3. IPSP, like EPSP is a local response and can be summated. IPSPs are caused by transmitters like GABA (gamma amino butyric acid), glycine, etc. IPSP reaches its peak at 11.5 ms after the application of stimulus, which then decreases exponentially. Ionic Basis IPSP is produced by opening of Cl− channels (Cl− enters into the cells along the concentration gradient). Opening of K+ cannels that result in K+ efflux can produce IPSP. Closure of Na+ or Ca2+ channels also produce IPSP. Slow IPSP Slow IPSPs are also observed in autonomic ganglia and cortical neurons. They usually occur due to increased K+ conductance. Nerve Potential For nerve impulses to be transmitted from neuron to neuron, the action potential must be generated and propagated along the nerve cell membrane. All these events depend on the activities of ion channels present on the membrane of the neurons. Neuronal Ion Channel Like any other cell membrane, neuronal membrane possesses numerous ion channels like Na+, K+, Ca2+, Cl−, etc. They are broadly categorized into three types: i. Nongated or leaky channels: The nongated or leaky channels of Na+, K+, Cl− are present throughout the neuronal membrane ii. Gated channels - voltage-gated channel: The voltage-gated Na+ channels are concentrated at the nodes of Ranvier. The voltage-gated Ca2+ channels are mainly present at the axon terminals, where they play important role in the secretion of neurotransmitters. - ligand-gated channel: Ligand-gated ion channels are present predominantly on dendritic spines, dendrites and cell body of the neuron. They are important for receiving information from other neurons at synaptic sites, in the form of released neurotransmitters. - mechanical gated channel: The mechanical-gated Na+ channels are involved in the genesis of receptor potential in the somatic sensory nerve endings. iii. ATP-driven pumps: Distribution of Na+ Channel In myelinated neurons, the number of Na+ channels per square micrometer of membrane in different segments of the neuron is as follows: 1. At cell body: 50–75 2. At initial segment: 350–500 3. On the surface of the myelin: 25 4. At the nodes of Ranvier: 2000–12,000 5. At the axon terminals: 20–75 Thus, the channels are concentrated in areas where the action potential is first initiated (initial segment) and in regions where it is regenerated (nodes of Ranvier) during its propagation. In unmyelinated neurons, about 110 Na+ channels are present per square micrometer of the axonal membrane. Abnormalities of channels are called channelopathies Terms used in Membrane Potentials Certain terms are used to explain the change in membrane potential relative to the resting membrane potential (RMP): 1. When there is a voltage difference between the inside and outside of the membrane, the membrane is said to be polarized. 2. When a stimulus allows influx of positive charges or efflux of negative charges, it decreases the membrane potential (i.e. the membrane potential approaches towards zero) and the stimulus is called a depolarizing stimulus. Thus, the membrane is said to be depolarized when the membrane potential becomes positive or less negative in relation to RMP. 3. After the depolarization phase, return of the potential towards the resting value is known as repolarization. 4. Similarly, as the interior of the cell becomes more negative in relation to RMP, due to influx of negative charges or removal of positive charges, the membrane is said to be hyperpolarized. In this state, the membrane potential is more negative in relation to RMP. Genesis of Nerve Potential The ability of the cells to generate action potential in their membrane is known as excitability. Nerve is a highly excitable tissue, which can be stimulated by electrical, chemical and mechanical forms of energy. When a stimulus is applied, it induces ions to flow across the membrane and alters the ionic balance on both sides of the membrane, producing a voltage change. With application of a stronger stimulus, much larger disturbance in ionic balance occurs. However, the ionic balance is promptly restored by 2 factors (repolarizing forces): 1. Diffusion of ions across the cell membrane 2. Increased activity of Na+-K+ ATPase. The voltage changes across the membrane generate electrical signals, which on recording show a wave like pattern. The transient and small voltage changes spread along the length of the nerve fiber and die out after some time. When the stimulus is strong enough, the response does not die out fast, rather, it travels along the whole length of the axon, being regenerated at regular intervals. This phenomenon is possible because the neuronal membrane is a biological membrane studded with different ion channels, whose activation time is modifiable with change in external environment. In the neuron, processing of information takes place chiefly in the cell body and to some extent in the dendrites. The message transmission occurs by means of generation and propagation of the electrical signals in the axon from one end to the other. These generated signals can be of two types:  Graded potentials: spread the signal over short distances,  Action potentials: transmit the message throughout the length of the plasma membrane. Another type of response is seen in neuronal membrane that is called local response. Electronic or Graded potential Definition Electrotonic potentials are local, nonpropagated potentials of small magnitude, in response to a depolarizing or hyperpolarizing stimulus of lesser strength. Types Electrotonic potentials are two types:  Catelectrotonic potential: When a membrane is electrically stimulated, the cathodal end of the stimulator evokes a depolarizing response called catelectrotonic potential.  Anelectrotonic potential: The hyperpolarizing potential produced due to stimulation at the anodal end is known as anelectrotonic potential. Concept In the resting state, negatively charged ions are lined along the interior of the membrane and positively charged ions are lined along the exterior of the membrane: 1. With the application of a cathodal stimulus of smaller strength to a small area of the membrane, few Na+ ions enter through the leaky sodium channels into the cell. 2. At that instant, at the site of stimulus, the inside of the membrane becomes positive compared to the previous resting state. 3. With application of greater strength of stimulus, more positive charges enter into the cell and the voltage change is larger. 4. The repolarizing forces try to neutralize the disturbance in RMP, created by the Na+ entry. K+ tends to come out of the cell and Cl− enters through the leaky channels to maintain the electrical neutrality. Also, Na+ moves away by diffusion from the site of stimulus. Moreover, activity of the Na+-K+ ATPase is increased pumping 3 Na+ out and 2 K+ in. All these lead to the gradual return of the membrane potential towards the resting value. In the neuron, graded potentials are recorded from the membranes of dendrites and cell body. Properties of Graded Potential 1. Graded in nature: The term graded potential comes from the fact that the potential change increases in a stepwise manner with application of increasing strength of stimulus, i.e. the magnitude of potential change is proportionate to the stimulus strength. 2. Decremental conduction: Graded potentials decay progressively with time and distance, which is known as decremental conduction: 3. Depolarizing or hyperpolarizing nature 4. Summation: if a second stimulus is applied before the potential produced by the first stimulus has disappeared, both the potential changes are added together producing a larger and/or prolonged wave in the recording. This happens due to the arrival of more Na+ ions at the site of stimulus before neutralization of all Na+ influx caused by the first stimulus. Similarly, the anelectrotonic potentials exhibit the property of summation. Forms of Graded Potentials Wherever a cell responds to a stimulus, graded potentials are produced along its membrane: 1. End-plate potential: recorded from skeletal muscle membrane at neuromuscular junctions. 2. Receptor potential: recorded from sensory nerve endings. 3.Synaptic potential: recorded from membrane of postsynaptic neurons at neuro-neuronal junctions. 4. Pacemaker potential: recorded from pacemaker cells in the heart, intestine, etc. and so on. Action Potential Definition Action potential is defined as a transient change in membrane potential of about 100 mV, which is conducted along the axon in an all-or-none fashion. It has following featues: 1. It is characterized by a gradual depolarization to threshold, and a rapid ascent in the membrane potential followed by a phase of repolarization. 2. It travels along the axon with the same shape and amplitude being regenerated at regular intervals. 3. It is also known as an impulse or spike potential Phases of Action Potential It has two phases: 1. The phase of depolarization is recorded as a sharp upward wave during which the membrane potential approaches zero and then attains a positive value. It consists of slow depolarization to threshold, rapid rising phase, overshoot and peak. During overshoot, the membrane potential crosses the zero or isopotential level and then at peak, it reaches a maximum potential of +35 mV. 2. The phase of repolarization is recorded as downstroke during which the membrane potential returns to the resting level. It includes a rapid falling phase and slower terminal part called after-depolarization. The phase of repolarization is followed by an afterhyperpolarization phase during which the membrane potential undershoots (becomes more negative) and then returns back to the resting level Ionic Basis of Action Potential The action potential is a fast depolarization (the upstroke), followed by repolarization back to the resting membrane potential  Resting membrane potential. At rest, the membrane potential is approximately -70 mV (cell interior negative). The K+ conductance or permeability is high and K+ channels are almost fully open, allowing K ions to diffuse out of the cell down the existing concentration gradient. This diffusion creates a K+ diffusion potential, which drives the membrane potential toward the K+ equilibrium potential. The conductance to Cl- (not shown) also is high, and, at rest, Cl- also is near electrochemical equilibrium. At rest, the Na+ conductance is low, and, thus, the resting membrane potential is far from the Na+ equilibrium potential.  Upstroke of the Action Potential: An inward current usually the result of current spread from action potentials at neighboring sites, causes depolarization of the nerve cell membrane to threshold, which occurs at approximately -60 mV. This initial depolarization causes rapid opening of the activation gates of the Na+ channel, and the Na+ conductance promptly increases and becomes even higher than the K+ conductance. The increase in Na+ conductance results in an inward Na+ current; the membrane potential is further depolarized toward, but does not quite reach, the Na+ equilibrium potential of +65 mV. Tetrodotoxin (a toxin from the Japanese puffer fish) and the local anesthetic lidocaine block these voltage- sensitive Na+ channels and prevent the occurrence of nerve action potentials.  Repolarization of the action potential. The upstroke is terminated, and the membrane potential repolarizes to the resting level as a result of two events. First, the inactivation gates on the Na+ channels respond to depolarization by closing, but their response is slower than the opening of the activation gates. Thus, after a delay, the inactivation gates close the Na+ channels, terminating the upstroke. Second, depolarization opens K+ channels and increases K+ conductance to a value even higher than occurs at rest. The combined effect of closing of the Na+ channels and greater opening of the K+ channels makes the K+ conductance much higher than the Na+ conductance. Thus, an outward K+ current results, and the membrane is repolarized. Tetra ethyl ammonium (TEA) blocks these voltage-gated K+ channels, the outward K+ current, and repolarization.  Hyperpolarizing after potential (undershoot). For a brief period following repolarization, the K conductance is higher than at rest, and the membrane potential is driven even closer to the K equilibrium potential (hyperpolarizing after potential). Eventually, the K conductance returns to the resting level, and the membrane potential depolarizes slightly, back to the resting membrane potential. The membrane is now ready, if stimulated, to generate another action potential. The Nerve Na+ Channel A voltage-gated Na+ channel is responsible for the upstroke of the action potential in nerve and skeletal muscle. This channel is an integral membrane protein, consisting of a large α subunit and two β subunits. The α-subunit has four domains, each of which has six transmembrane α-helices. The repeats of transmembrane α-helices surround a central pore, through which Na ions can flow (if the channel’s gates are open). The basic assumption of this model is that in order for Na+ to move through the channel, both gates on the channel must be open. Recall how these gates respond to depolarization: The activation gate opens quickly, and the inactivation gate closes after a time delay.  At rest, the activation gate is closed. Although the inactivation gate is open (because the membrane potential is hyperpolarized), Na+ cannot move through the channel.  During the upstroke of the action potential, depolarization to threshold causes the activation gate to open quickly. The inactivation gate is still open because it responds to depolarization more slowly than the activation gate. Thus, both gates are open briefly, and Na+ can flow through the channel into the cell, causing further depolarization (the upstroke).  At the peak of the action potential, the slow inactivation gate finally responds and closes, and the channel itself is closed. Repolarization begins. When the membrane potential has repolarized back to its resting level, the activation gate will be closed and the inactivation gate will be open, both in their original positions. Initiation and Propagation of Action Potential Initiation of Action Potential The production of action potentials requires the presence of large number of voltage-gated ion channels that are present mostly on the axons. Therefore, it is the axon, not the cell body or the dendrites that generate and conduct the action potentials: 1. The action potential is first initiated in the specialized areas in the axon called the first node of Ranvier in sensory neurons and initial segment-axon hillock area in motor neurons. 2. These areas are known as trigger zones that have a very high concentration of voltage-gated sodium and potassium channels. 3. The synaptic potential generated at the dendrites and, or the cell body is integrated by the cell body and transmitted to the axon hillock. 4. If this potential is sufficient to depolarize the membrane of the axon hillock to firing level, the membrane easily fires an action potential. Propagation of Action Potential Once formed, the action potential is regenerated at regular intervals to be transmitted from the initial segment of the axon to the axon terminal. This is known as the propagation of action potential. In myelinated axon, the speed and mode of propagation of action potential is different from that in unmyelinated axon. The speed of conduction of the impulse depends on two factors: 1. Myelination: Conduction velocity is more in myelinated axon and is proportionate to the degree of myelination. 2. Diameter of the axon: Conduction velocity is proportionate to the diameter of the fiber. Fibers with larger diameter have faster rate of conduction. The large diameter fibers have less cytoplasmic resistance. So, the flow of ions across the membrane is easier. In Unmyelinated Axon At the site of genesis of an action potential, large influx of positive charges into the membrane occurs, which is known as current sink. The positive charges diffuse away from the site of accumulation. The adjacent membrane, which is in its resting state, has a potential of –70 mV: 1. This potential difference allows the positive charges to flow toward the adjacent negative area. Consequently, the potential of the adjacent membrane decreases and reaches the threshold value, as the fraction of Na+ ions that move to the nearby negative area are sufficient enough to bring the adjacent membrane to the firing level. This results in opening of the voltage gated Na+ channels present in that area, firing an action potential. 2. Similarly, from the site of second action potential, positive charges flow to the adjacent resting membrane and decrease its potential to the threshold level. This activates the voltage gated Na+ channels present in that part of the membrane resulting in another action potential. 3. In this manner, each point of the membrane gets depolarized to the firing level and produces an action potential. 4. As the depolarization and repolarization phases of the ensuing action potentials go on, there is a sequential opening and closing of sodium and potassium channels along the axonal membrane. 5. The action potential does not move by itself but helps to generate a new action potential in the membrane ahead of it. As the number of voltage gated Na+ and K+ channels are distributed uniformly along the axon, the action potential arriving at the end of the axon is almost identical in appearance to the initial one. Thus, due to the local current flow produced following an action potential, there occurs serial depolarization of the adjacent membrane to the firing level and action potential travels, being successively regenerated along the membrane in an all-or-none manner. 6. At the same time, the exterior of the membrane which becomes negative due to current sink attracts flow of positive charges from the adjacent regions toward the site of application of stimulus. Thus, on both sides of the site of action potential, a circular pattern of current flow occurs across the membrane; i.e. inside the membrane, positive charges flow away from the site of action potential, whereas outside the membrane, positive charges flow towards the site of action potential. This circular pattern of current flow tries to restore the resting potential of the membrane where the action potential was previously generated. In Myelinated Axon (Saltatory Conduction) There are few voltage gated Na+ channels on the surface of the myelin: 1. Myelin acts as an insulator and does not allow free flow of ions across the membrane. Therefore, as the positive charges flow from the site of action potential to the adjacent area, large Na+ influx (as occurs during an action potential) does not occur in the myelinated portion of the membrane, though it may attend the threshold potential of –55 mV. Also, in the myelin sheath, the concentration of positive charges does not decrease fast because of less ‘leakage’. This helps the charges to spread farther along the axon. 2. The local current (the positive charges) travels like a graded potential and dies away 37% of its maximal strength over a distance of about 3 mm. 3. As the internodal distance is 1–2 mm, the local current definitely arrives at the adjacent node of Ranvier and decreases its membrane potential. Most importantly, the voltage gated Na+ channels are present in large numbers at the nodes of Ranvier. Therefore, as soon as the nodal membrane gets depolarized to threshold level, an action potential is quickly fired. 4. Thus, in the myelinated axon, the action potential is generated at each node of Ranvier. 5. Because the action potential rapidly proceeds from one node to the next and pause at each node to get regenerated, the mode of propagation of action potential in myelinated axon is known as salutatory conduction (Latin word ‘saltare’ means to jump). Advantages in Myelinated Axon In myelinated axon, the velocity of conduction is faster. Besides, myelination also helps to conserves energy. Since the ionic flux occurs only at the nodes of Ranvier, the total membrane area across which ionic balance has to be restored is much less compared to the unmyelinated axon. Therefore, in unmyelinated axons, voltage-gated channels open throughout the axonal length causing activation of larger number of Na+-K+ ATPase and higher expenditure of energy. Direction of Propagation of Action Potential In the motor neuron, the action potential is conducted from axon hillock toward axon terminal. In the sensory neuron, it propagates from the first node of Ranvier toward CNS. This is called anterograde conduction of impulse: 1. The axon contains a large number of voltage gated Na+ channels that promotes in quick generation of an action potential in the axonal membrane next to the trigger zone. 2. The action potential does not travel from the axon back toward the trigger zone. This is because; following depolarization, the area on the membrane where action potential was produced becomes refractory. 3. Therefore, though local currents from the site of next action potential tend to bring the membrane toward threshold value, the membrane does not fire an action potential, as the sodium channels remain inactivated. 4. Hence, the action potential can be conducted only in the direction away from the site of previous action potential. 5. The action potential can spread from the point of stimulus in both directions along the axon, if it is initiated between trigger zone and axon terminal. RENAL SYSTEM The kidneys play a vital role in homeostatic functions of the body. Therefore, impairment of kidney functions leads to many homeostatic abnormalities. Extracellular fluid (ECF) compartment is the interface between the external and the internal (cellular) milieus of living creatures. Water, minerals, nutrients and gases pass through the ECF before entering the cellular compartment, and cellular waste products pass through the ECF before being excreted from the body. Hence, maintenance of ECF volume and composition, the aim of many homeostatic mechanisms, is vital for organ functions. Kidneys play principal role in this homeostasis. Functions of Kidney  Urine formation and excretion of waste products: The primary function of the kidneys is to excrete waste products of metabolisms from the body such as urea, creatinine, uric acid, etc. dissolved in urine. Kidneys form urine and excrete many toxic waste products from the body dissolved in urine. Thus, kidneys prevent their accumulation to a dangerous level in the body.  Regulation of ECF volume: Kidneys play an important role in regulation of ECF volume of the body. Many hormones such as aldosterone, ADH, ANP, angiotensin etc. involved in regulation of ECF volume act on kidney tubules to achieve this function. These hormones modify reabsorption of sodium and water from kidneys to control ECF volume.  Regulation of blood pressure (BP): Kidneys contribute mainly to long-term regulation of arterial volume and pressure. Renin secreted from kidney activates reninangiotensin- aldosterone axis that plays an important role in regulation of BP. Many hormones act on kidney to regulate blood volume and pressure. Kidneys have also their intrinsic mechanisms to alter sodium and water excretion to regulate BP.  Regulation of electrolyte composition of body fluids: Composition of electrolytes in ECF is mainly the function of kidney. Excretion and reabsorption of electrolytes from kidneys directly influence their concentration in ECF. Kidneys also contribute to vitamin D synthesis that controls plasma calcium concentration.  Acid-base balance: Kidneys contribute significantly to acid-base balance by controlling bicarbonate excretion and H+ secretion. Thus, it controls blood pH and pH of other body fluids. Therefore, kidney abnormalities may cause metabolic acidosis or alkalosis.  Regulation of plasma osmolality: By controlling NaCl and water reabsorption, kidneys control plasma osmolality. Change in plasma osmolality provides feedback signal for secretion of ADH that acts on kidney to regulate the osmolality.  Regulation of erythropoiesis: Erythropoietin, the major regulator of erythropoiesis is secreted from interstitial cells in the peritubular capillary bed of kidney. Therefore, kidney diseases result in anemia.  Endocrine functions: Kidney secretes thromboxane A2 and prostaglandins, in addition to the secretion of erythropoietin. Kidneys secrete renin that activates renin-angiotensin system. Kidneys also form calcitriol (1,25-dihydroxycholecalciferol), the active form of vitamin D3 from 25-hydroxycholecalciferol.  Gluconeogenesis: Though kidneys are not the primary site of gluconeogenesis, in starvations, synthesis of glucose from noncarbohydrate sources, especially from glutamine occurs in these organs. ANATOMY AND BLOOD SUPPLY Kidneys are bean shaped paired retroperitoneal organs present in the posterior part of the abdomen just above the waist between the last thoracic and third lumbar vertebrae. The right kidney is slightly lower in position due to the presence of liver on the right side.  Size of each kidney in adult is roughly about the size of one’s fist (11 cm in length and 6 cm in width), and the weight is about 150 g.  Kidneys are covered by a thick capsule called renal capsule.  The medial border of kidney is concaved and the center of the concavity is called renal hilus, from which the ureter comes out of the organ Three Main Regions of Kidney In sagittal section, the kidneys have three main regions: (1) The cortex is the outer region, located just under the kidney capsule. The cortex is granular in appearance and contains all glomeruli, convoluted tubules and cortical portion of collecting ducts (2) The medulla is a central region, divided into an outer medulla and an inner medulla. The outer medulla has an outer stripe and an inner stripe. The medulla is striated in appearance due to presence of loop of Henle, medullary portion of collecting duct and blood vessels that are arranged in parallel. (3) The papilla is the innermost tip of the inner medulla and empties into pouches called minor and major calyces, which are extensions of the ureter. The urine from each kidney drains into a ureter and is transported to the bladder for storage and subsequent elimination. Structure of the Nephron The basic structural and functional units of the kidney are nephrons. Each kidney contains approximately 1.2 million nephrons. A nephron consists of  a glomerulus  a renal tubule. The glomerulus is a glomerular capillary network, which emerges from an afferent arteriole. Glomerular capillaries are surrounded by Bowman’s capsule (or Bowman’s space), which is continuous with the first portion of the nephron. Blood is ultrafiltered across the glomerular capillaries into Bowman’s space, which is the first step in urine formation. The remainder of the nephron is a tubular structure lined with epithelial cells which serve the functions of reabsorption and secretion. The nephron or renal tubule comprises the following segments (beginning with Bowman’s space): 1. The proximal convoluted tubule 2. The proximal straight tubule 3. The loop of Henle (which contains a thin descending limb, a thin ascending limb, and a thick ascending limb) 4. The distal convoluted tubule 5. The collecting ducts. Each segment of the nephron is functionally distinct, and the epithelial cells lining each segment have a different ultrastructure. For example, the cells of the proximal convoluted tubule are unique in having an extensive development of microvilli, called a brush border, on their luminal side. The brush border provides a large surface area for the major reabsorptive function of the proximal convoluted tubule. The total length of the nephron ranges from 45 to 65 mm. Secretory Cells of Kidney The secretory or endocrine cells in kidney are mainly two types: 1. Juxtaglomerular (JG cells) cells: JG cells secrete renin that activates renin-angiotensin system. 2. Interstitial cells (IS cells): Three are two types of interstitial cells.  Cortical interstitial cells: are of two types:  Phagocytic cell  fibroblast-like cells: secrete erythropoietin.  Medullary interstitial cells: are of two types  Type-I medullary interstitial cells: secrete prostaglandins, especially PGE2  Type-II medullary interstitial cell Types of nephrons There are two types of nephron which are distinguished by the location of their glomeruli 1. Superficial cortical nephrons:  Have their glomeruli in the outer cortex.  Size of glomerulus usually small  It is 85% of total nephron  These nephrons have relatively short loops of henle  Length of thin limb of loop of henle is shorter and thin ascending is almost absent  Rate of filtration is slow  Efferent arteriole forms peritubular capillaries  Efficiency in concentrating urine is less  Renin content is more  The main function is urine formation and excretion of waste products 2. Juxtamedullary nephrons.  Have their glomeruli near the corticomedullary border.  Size of glomeruli are usually large  It is 15% of total nephron  These nephrons have relatively long loops of henle  Length of thin limb of loop of henle is longer and thin limb has ascending and descending part  Rate of filtration is high  Efferent arteriole forms peritubular capillaries and vasa recta  Efficiency in concentrating urine is more  Renin content is less  The main function is urine concentration Renal Vasculature Blood enters each kidney via a renal artery, which branches into interlobar arteries, arcuate arteries, and then cortical radial arteries. The smallest arteries subdivide into the first set of arterioles, the afferent arterioles. The afferent arterioles deliver blood to the first capillary network, the glomerular capillaries, across which ultrafiltration occurs. Blood leaves the glomerular capillaries via a second set of arterioles, the efferent arterioles, which deliver blood to a second capillary network, the peritubular capillaries. The peritubular capillaries surround the nephrons. Solutes and water are reabsorbed into the peritubular capillaries, and a few solutes are secreted from the peritubular capillaries. Blood from the peritubular capillaries flows into small veins and then into the renal vein. Functions of Vasa Recta 1. It provides oxygen and nutrients to the nephron segments. 2. It delivers substances to the nephron for secretion into the tubular lumen. 3. It serves as a pathway for the return of reabsorbed water and solutes to the circulatory system. 4. It participates in concentration (as counter current exchange) and dilution of urine. Juxtaglomeular Apparatus Structure The thick ascending limb of loop of Henle when comes in contact with the glomerulus of the same renal corpuscle, structural modifications occur in the tubule and afferent and efferent arterioles The entire modified structure (tubular and vascular components and the cells between them) is called juxtaglomerular apparatus (JGA), which includes: 1. Macula densa of the thick ascending limb of loop of henle, 2. Juxtaglomerular cells (the modified muscle cells mainly of afferent arterioles), and 3. Lacis cells (extraglomerular mesangial cells). Macula Densa Macula densa cells are modified epithelial cells of the thick ascending limb of LOH when it comes in contact with the afferent and efferent arterioles. 1. The terminal portion of the thick ascending limb of loop of henle that passes through the angle formed by afferent and efferent arterioles of the same nephron possesses this tubular epithelial modification. This appears as a dense area (hence, called macula densa) in the tubule as epithelial cells are densely packed in this region. 2. Macula densa acts as the sensor that monitors the change in ionic composition and rate of flow of the tubular fluid in the lumen of the tubule. 3. It provides appropriate feedback signal to renal corpuscle to change the rate of filtration so as to meet the need of the kidney functions. 4. Therefore, this is an important component in the tubuloglomerular feedback circuit. Juxtaglomerular Cells Juxtaglomerular (JG) cells are the granular epitheloid cells present mainly in the tunica media of the afferent arteriole (few are also present in efferent arteriole) that come in contact with the terminal part of thick ascending limb of loop of henle. 1. In fact, these granular cells are modified vascular smooth muscle cells with an epithelioid appearance. 2. The cells are highly granular as they contain many secretory granules. 3. They are also called Polkissen cells. 4. JG cells secrete renin that activates renin-angiotensin system. Lacis Cells Lacis cells are present in the triangular space formed by efferent and afferent arterioles and the macula densa. Lacis cells are the mesangial cells present outside the glomerulus; hence called extraglomerular mesangial cells. These are agranular cells that secrete some quantity of renin and erythropoietin. Functions of JG Apparatus 1. JG cells secrete renin that activates renin-angiotensin system, which is involved primarily in the regulation of blood volume and pressure. 2. Macula densa cells act as sensor that detects the change in rate of flow and volume of flow in the tubule, and composition of tubular fluid. This provides feedback signal to the glomerulus to change the rate of filtration, which forms the physiological basis of tubuloglomerular feedback. Thus, they control glomerular filtration. 3. Lacis cells secrete renin and erythropoietin RENAL CLEARANCE Renal clearance is the volume of plasma completely cleared of a substance by the kidneys per unit time. The higher the renal clearance, the more plasma that is cleared of the substance. Substances with the highest renal clearances may be completely removed on a single pass of blood through the kidneys; substances with the lowest renal clearances are not removed at all. The equation for renal clearance is as follows: C = [U] x × V [P]x Thus, renal clearance is the ratio of urinary excretion ([U]x ×V) to plasma concentration. For a given plasma concentration, renal clearance of a substance increases as the urinary excretion increases. Again, the units of clearance are volume per unit time (e.g., mL/min; L/hour; L/day), which means the volume of plasma cleared of the substance per unit time. Clearance of Various Substance Renal clearance can be calculated for any substance. Depending on the characteristics of the substance and its renal handling, renal clearance can vary from zero to greater than 600 mL/min. For example, renal clearance of albumin is approximately zero because, normally, albumin is not filtered across the glomerular capillaries. The renal clearance of glucose is also zero, although for a different reason: Glucose is filtered and then completely reabsorbed back into the bloodstream. Other substances such as Na+, urea, phosphate, and Cl− have clearances that are higher than zero because they are filtered and partially reabsorbed. Inulin, a fructose polymer, is a special case. Inulin is freely filtered across the glomerular capillaries, but it is neither reabsorbed nor secreted; therefore, its clearance measures the glomerular filtration rate. Organic acids such as para- aminohippuric acid (PAH) have the highest clearances of all substances because they are both filtered and secreted. RENAL BLOOD FLOW The kidneys receive about 25% of the cardiac output, which is among the highest of all the organ systems. Thus, in a person whose cardiac output is 5 L/min, renal blood flow (RBF) is 1.25 L/min or 1800 L/day! Such high rates of RBF are not surprising in light of the central role the kidneys play in maintaining the volume and composition of the body fluids. Importance of Renal Blood Flow The flow of blood through kidneys serves following important functions: 1. Supplies oxygen, nutrients, and hormones that control kidney functions. 2. Delivers metabolites and waste products to the kidney for their excretion in the urine. 3. Controls concentration and dilution of urine. 4. Influences solute and water reabsorption from kidney. 5. Determines GFR (RBF is the main determinant of GFR). Regulation of Renal Blood Flow As with blood flow in any organ, RBF (Q) is directly proportional to the pressure gradient (ΔP) between the renal artery and the renal vein, and it is inversely proportional to the resistance (R) of the renal vasculature. (Recall that Q = ΔP/R. Recall, also, that resistance is provided mainly by the arterioles.) The kidneys are unusual, however, in that there are two sets of arterioles, the afferent and the efferent. The major mechanism for changing blood flow is by changing arteriolar resistance. In the kidney, this can be accomplished by changing afferent arteriolar resistance and/ or efferent arteriolar resistance  Sympathetic nervous system and circulating catecholamines. Both afferent and efferent arterioles are innervated by sympathetic nerve fibers that produce vasoconstriction by activating α1 receptors. However, because there are far more α1 receptors on afferent arterioles, increased sympathetic nerve activity causes a decrease in both RBF and GFR. When renal α1 receptors are activated by this increase in sympathetic activity, there is vasoconstriction of afferent arterioles that leads to a decrease in RBF and GFR.  Angiotensin II. Angiotensin II is a potent vasoconstrictor of both afferent and efferent arterioles. The effect of angiotensin on RBF is clear: It constricts both sets of arterioles, increases resistance, and decreases blood flow. However, efferent arterioles are more sensitive to angiotensin II than afferent arterioles, and this difference in sensitivity has consequences for its effect on GFR (see the discussion on regulation of GFR). Briefly, low levels of angiotensin II produce an increase in GFR by constricting efferent arterioles, while high levels of angiotensin II produce a decrease in GFR by constricting both afferent and efferent arterioles. In hemorrhage, blood loss leads to decreased arterial pressure, which activates the renin-angiotensin-aldosterone system. The high level of angiotensin II, together with increased sympathetic nerve activity, constricts afferent and efferent arterioles and causes a decrease in RBF and GFR.  Atrial natriuretic peptide (ANP). ANP and related substances such as brain natriuretic peptide (BNP) cause dilation of afferent arterioles and constriction of efferent arterioles. Because the dilatory effect of ANP on afferent arterioles is greater than the constrictor effect on efferent arterioles, there is an overall decrease in renal vascular resistance and resulting increase in RBF. Dilation of afferent arterioles and constriction of efferent arterioles both lead to increased GFR (see discussion on regulation of GFR).  Prostaglandins. Several prostaglandins (e.g., prostaglandin E2 and prostaglandin I2) are produced locally in the kidneys and cause vasodilation of both afferent and efferent arterioles. The same stimuli that activate the sympathetic nervous system and increase angiotensin II levels in hemorrhage also activate local renal prostaglandin production. Although these actions may seem contradictory, the vasodilatory effects of prostaglandins are clearly protective for RBF. Thus, prostaglandins modulate the vasoconstriction produced by the sympathetic nervous system and angiotensin II. Unopposed, this vasoconstriction can cause a profound reduction in RBF, resulting in renal failure. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit synthesis of prostaglandins and, therefore, interfere with the protective effects of prostaglandins on renal function following a hemorrhage.  Dopamine. Dopamine, a precursor of norepinephrine, has selective actions on arterioles in several vascular beds. At low levels, dopamine dilates cerebral, cardiac, splanchnic, and renal arterioles, and it constricts skeletal muscle and cutaneous arterioles. Thus, a low dosage of dopamine can be administered in the treatment of hemorrhage because of its protective (vasodilatory) effect on blood flow in several critical organs including the kidneys. Autoregulation of Renal Blood Flow RBF is autoregulated over a wide range of mean arterial pressures (Pa). Renal arterial pressure can vary from 80 to 200 mm Hg, yet RBF will be kept constant. Only when renal arterial pressure decreases to less than 80 mm Hg does RBF also decrease. The only way to maintain this constancy of blood flow in the face of changing arterial pressure is by varying the resistance of the arterioles. Thus, as renal arterial pressure increases or decreases, renal resistance must increase or decrease proportionately (recall that Q = ΔP/R). For renal autoregulation, it is believed that resistance is controlled primarily at the level of the afferent arteriole, rather than the efferent arteriole. The mechanism of autoregulation is not completely understood. Clearly, the autonomic nervous system is not involved because a denervated (e.g., transplanted) kidney autoregulates as well as an intact kidney. The major theories explaining renal autoregulation are a myogenic mechanism and tubuloglomerular feedback. ♦ Myogenic hypothesis. The myogenic hypothesis states that increased arterial pressure stretches the blood vessels, which causes reflex contraction of smooth muscle in the blood vessel walls and consequently increased resistance to blood flow. The mechanism of stretch-induced contraction involves the opening of stretch-activated calcium (Ca2+) channels in the smooth muscle cell membranes. When these channels are open, more Ca2+ enters vascular smooth muscle cells, leading to more tension in the blood vessel wall. The myogenic hypothesis explains autoregulation of RBF as follows: Increases in renal arterial pressure stretch the walls of the afferent arterioles, which respond by contracting. Afferent arteriolar contraction leads to increased afferent arteriolar resistance. The increase in resistance then balances the increase in arterial pressure, and RBF is kept constant. ♦ Tubuloglomerular feedback. Tubuloglomerular feedback is also a mechanism for autoregulation explained as follows: When renal arterial pressure increases, both RBF and GFR increase. The increase in GFR results in increased delivery of solute and water to the macula densa region of the early distal tubule, which senses some component of the increased delivered load. The macula densa, which is a part of the juxtaglomerular apparatus, responds to the increased delivered load by secreting a vasoactive substance that constricts afferent arterioles via a paracrine mechanism. Local vasoconstriction of afferent arterioles then reduces RBF and GFR back to normal; that is, there is autoregulation. There are two major unanswered questions concerning the mechanism of tubuloglomerular feedback: MEASUREMENT OF RENAL PLASMA FLOW AND RENAL BLOOD FLOW Renal plasma flow (RPF) can be estimated from the clearance of an organic acid para- aminohippuric acid (PAH). Renal blood flow (RBF) is calculated from the RPF and the hematocrit. Fick principle The Fick principle states that the amount of a substance entering an organ equals the amount of the substance leaving the organ (assuming that the substance is that the amount of degraded by the organ). Applied to the kidney, the Fick principle states that the amount of a substance entering the kidney via the renal artery equals the amount of the substance leaving the kidney via the renal vein plus the amount excreted in the urine. PAH is the substance used to measure RPF with the Fick principle, and the derivation is as follows: Amount of PAH entering kidney= Amount of PAH leaving kidney Amount of PAH entering kidney = [RA]PAH × RPF Amount of PAH leaving kidney [RV] PAH × RPF + [U] PAH ×V substituting [RA]PAH × RPF= [RV] PAH × RPF +[U] PAH ×V Solving for RPF [RA]PAH RPF- [RV] PAH RPF =[U] PAH V RPF([RA]PAH - [RV]PAH) = [U] PAH V RPF = [U] PAH V ([RA]PAH - [RV]PAH) PAH has the following characteristics that make it the ideal substance for measuring RPF: (1) PAH is neither metabolized nor synthesized by the kidney. (2) PAH does not alter RPF. (3) The kidneys extract (remove) most of the PAH from renal arterial blood by a combination of filtration and secretion. As a result, almost all of the PAH entering the kidney via the renal artery is excreted in urine, leaving little in the renal vein. Because the renal vein concentration of PAH is nearly zero, the denominator of the previous equation ([RA]PAH − [RV]PAH) is large and, therefore, can be measured accurately. To elaborate this point, compare a substance such as glucose, which is not removed from renal arterial blood at all. Renal vein blood will have the same glucose concentration as renal artery blood, and the denominator of the equation will be zero, which is not mathematically permissible. Clearly, glucose cannot be used to measure RPF. (4) No organ, other than the kidney, extracts PAH, so the PAH concentration in the renal artery is equal to the PAH concentration in any peripheral vein. Peripheral venous blood can be sampled easily, whereas renal arterial blood cannot Measuring of Renal Blood Flow RBF is calculated from RPF and the hematocrit (Hct). The formula used to calculate RBF is as follows: Thus, RBF is the RPF divided by 1 minus the hematocrit, where hematocrit is the fraction of blood volume that is occupied by red blood cells, and 1 − hematocrit is the fraction of blood volume that is occupied by plasma. URINE FORMATION Steps Involve in Urine Formation 1. Glomerular Filtration 2. Reabsorption 3. Secretion Glomerular Filtration Glomerular filtration is the first step in the formation of urine. As the renal blood flow enters the glomerular capillaries, a portion of that blood is filtered into Bowman’s space, the first part of the nephron. The fluid that is filtered is similar to interstitial fluid and is called an ultrafiltrate. The ultrafiltrate contains water and all of the small solutes of blood, but it does not contain proteins and blood cells. The forces responsible for glomerular filtration are similar to the forces that operate in systemic capillaries—the Starling forces. There are differences, however, in the characteristics and surface area of the glomerular capillary barrier, making the glomerular filtration rates much higher than the filtration rates across systemic capillaries. Characteristics of the Glomerular Filtration Barrier The physical characteristics of the glomerular capillary wall determine both the rate of glomerular filtration and the characteristics of the glomerular filtrate. These characteristics determine what is filtered and how much is filtered into Bowman’s space. Layers of Glomerular Capillary Three layers constituted glomerular capillary wall 1. Endothelium 2. Basement membrane 3. Epithelium Endothelium: The endothelial cell layer has pores 70 to 100 nanometers (nm) in diameter. Because these pores are relatively large, fluid, dissolved solutes, and plasma proteins all are filtered across this layer of the glomerular capillary barrier. On the other hand, the pores are not so large that blood cells can be filtered. Basement membrane: The basement membrane has three layers.  The lamina rara interna is fused to the endothelium  The lamina densa is located in the middle of the basement membrane  The lamina rara externa is fused to the epithelial cell layer. The multilayered basement membrane does not permit filtration of plasma proteins and, therefore, constitutes the most significant barrier of the glomerular capillary. Epithelium: The epithelial cell layer consists of specialized cells called podocytes, which are attached to the basement membrane by foot processes. Between the foot processes are filtration slits, 25 to 60 nm in diameter, which are bridged by thin diaphragms. Because of the relatively small size of the filtration slits, the epithelial layer (in addition to the basement membrane) also is considered an important barrier to filtration. Starling Forces Across the Glomerular Capillaries The pressures that drive fluid movement across the glomerular capillary wall are the Starling pressures, or Starling forces. Theoretically, there are four Starling pressures: 1. Two hydrostatic pressures (one in capillary blood and one in interstitial fluid) 2. Two oncotic pressures (one in capillary blood and one in interstitial fluid). Fluid movement across the glomerular capillary wall is glomerular filtration. It is driven by the Starling pressures across the wall and, with the assumption that the oncotic pressure of Bowman’s space is zero, is described by the Starling equation: GFR = Kf ( PGC - PBS ) – πGC  Kf, filtration coefficient, is the water permeability or hydraulic conductance of the glomerular capillary wall. The two factors that contribute to Kf are the water permeability per unit of surface area and the total surface area.  PGC, hydrostatic pressure in glomerular capillaries, is a force favoring filtration.  PBS, hydrostatic pressure in Bowman’s space, is a force opposing filtration.  πGC, oncotic pressure in glomerular capillaries, is another force opposing filtration. Measurement of Glomerular Filtration Rate GFR is measured by the clearance of a glomerular marker. A glomerular marker has the following three characteristics: (1) It must be freely filtered across the glomerular capillaries, with no size or charge restrictions; (2) it cannot be reabsorbed or secreted by the renal tubule (3) when infused, it cannot alter the GFR. Thus, the properties of the ideal glomerular marker differ from those of a marker substance used to measure RPF (i.e., PAH). The ideal glomerular marker is inulin. It is neither reabsorbed nor secreted by the renal tubular cells. Thus, the amount of inulin filtered across the glomerular capillaries is exactly equal to the amount of inulin that is excreted in the urine. The clearance of inulin equals the GFR, as expressed in the following equation: Inulin is the only perfect glomerular marker; no other marker is perfect. Both blood urea nitrogen (BUN) and serum creatinine concentration can be used to estimate GFR because both urea and creatinine are filtered across the glomerular capillaries. Factors Affecting GFR The GFR is influenced by factors that alter renal blood flow, pressure gradients, glomerular capillary permeability and surface area for filtration: 1. Change in renal blood flow: Increased blood flow to kidney increases the delivery of blood to glomerulus that promotes filtration and conversely decreased flow decreases filtration. Thus, renal vasodilation maintains GFR. 2. Glomerular capillary hydrostatic pressure: Hydrostatic pressure in glomerular capillary depends on the amount of blood delivered to and the amount of blood drained from the glomerulus: a. Afferent arteriolar dilation or efferent arteriolar constriction increases capillary hydrostatic pressure and therefore, increases GFR. b. Conversely, afferent arteriolar constriction or efferent arteriolar dilation decreases GFR. 3. Change in capsular hydrostatic pressure: Hydrostatic pressure in the Bowman’s capsule and tubule opposes filtration. Tubular obstruction increases tubular hydrostatic pressure and therefore decreases GFR. 4. Oncotic pressure: Osmotic pressure in glomerular capillaries due to plasma proteins opposes filtration. Therefore, hypoproteinemia results in more GFR. Conversely, dehydration decreases GFR and urine formation. 5. Glomerular capillary permeability: Integrity of glomerular capillary is an important determinant of GFR. Increased capillary permeability increases GFR as occurs in glomerulonephritis. 6. Effective filtration surface area: Size of filtration area depends on mesangial cells: a. Mesangial cell contraction distorts the capillary lumen and decreases the area available for filtration. b. Conversely, relaxation of mesangial cells increases filtration. c. Many hormones and chemicals control GFR by altering mesangial cell activity. 7. Size, shape and electrical charge of the macromolecules Molecular size determines the filterability of the substance: a. Any substance having molecular weight less than 10,000 can be freely filtered by the glomerular filtration barrier and molecules with weight more than 10,000 have restricted filterability (Table 77.2). b. Most of the proteins in plasma are larger molecules and therefore can not be filtered. Also, the molecular shape influences filterability. c. Slender and supple molecules can easily pass through than the spherical and rigid molecules. d. Due to the presence of negatively charged particles in all the three layers of glomerular filtration barrier, molecules with negative charges can not easily be filtered, whereas neutral and cationic substances can do so. Conditions that Altars GFR GFR changes in different physiological and non-physiological conditions. The changes are due to the change in renal blood flow, glomerular oncotic pressure, glomerular hydrostatic pressure, change in plasma protein concentration, etc.  Exercise: GFR decreases in exercise due to sympathetic stimulation that causes more afferent arteriolar constriction than constriction of efferent arteriole.  Pregnancy: In pregnancy, RBF and GFR increase. RBF increases due to increase in blood volume, cardiac output and decreased renal vascular resistance. GFR increases mostly secondary to increase in RBF. However, hormonal changes also a play a role. About 40– 50% increase of GFR occurs in second and third trimesters of pregnancy.  Posture: Maintaining body in standing position for a longer duration decreases GFR due to sympathetic stimulation and decreased effective blood volume (pooling of blood in veins of lower limbs and abdomen). Conversely, supine posture increases GFR.  Sleep: GFR is usually less during sleep due to decreased circulatory activity. However, supine position maintains GFR.  Weather: GFR is more in rainy season and less in summer. In summer, decreased ECF volume decreases GFR. In winter and rainy season, GFR is more due to decreased loss of water from the body and less humidity.  Gender: GFR is less in females than in males.  Age: GFR decreases in geriatric age group due to functional loss of nephrons. GFR is also less in children.  Food Intake: Diet rich in proteins increases GFR. Filtration Fraction The filtration fraction expresses the relationship between the glomerular filtration rate (GFR) and renal plasma flow (RPF). The filtration fraction is given by the following equation: In other words, the filtration fraction is that fraction of the RPF that is filtered across the glomerular capillaries. The value for the filtration fraction is normally about 0.20, or 20%. That is, 20% of the RPF is filtered and 80% is not filtered. The 80% of RPF that is not filtered leaves the glomerular capillaries via the efferent arterioles and becomes the peritubular capillary blood flow. TUBULAR FUNCTIONS Tubular exchange of water and electrolytes finally determines the volume and composition of urine. Thus, tubular mechanisms are most important processes in determination in urine volume and composition. By modulating the reabsorption and secretion of substances of its luminal fluid, renal tubule plays an important role in the control of composition, osmolality, pH and volume of ECF. Common Principles of Tubular Functions The major function of tubule is to reabsorb water and solutes from the tubular fluid, which is crucial for water and electrolyte homeostasis of the body. These transport mechanisms for various substances are different in different parts of the kidney tubule. Transport Mechanism Processes of transport across tubular epithelium can be broadly divided into two categories:  Passive  Active. Transport of solutes involves both passive and active processes, whereas water reabsorption is a passive phenomenon Passive Transport Mechanisms The passive transport mechanisms include diffusion, facilitated diffusion, solvent drag and osmosis. Diffusion The solutes are transported by means of diffusion from their area of higher concentration to the area of lower concentration. This is the transport along the chemical gradient. Especially, uncharged solutes like glucose are transported by this mechanism. However, though charged solutes especially ions are also transported by diffusion, their electrical gradient greatly influences this passive transport. Facilitated Diffusion In this transport mechanism, a specific carrier protein in the membrane facilitates the process of diffusion. Reabsorption of glucose via glucose transporter is an example of facilitated diffusion. Sodium and potassium ions are also reabsorbed from kidney tubule through the water, filled channels created by the carrier proteins. Transport of glucose, proteins and urea from the tubular fluid are other examples of facilitated diffusion. Solvent Drag When bulk amount of water is reabsorbed, the solutes dissolved in water are also transported along with water across the tubular epithelium. This process is called solvent drag. This contributes to reabsorption of substantial amount of solutes in the proximal tubule. Osmosis When a considerable amount of osmotically active solute is transported, water is reabsorbed along with it to maintain the osmotic balance. This is the major mechanism for reabsorption of water from the tubular lumen. For example, water reabsorption follows reabsorption of Na+ and Cl– from the tubular fluid. Conversely, increased osmolality of tubular fluid increases water excretion, known as osmotic diuresis Active Transport Mechanisms Transport of solutes is considered to be active when ATP is utilized in the process. In this mechanism, solutes are transported from the area of lower concentration to the area of higher concentration. The best example of active transport mechanism is the Na+‑K+ pump. 1. The Na+‑K+ ATPase is mainly located in the basolateral membrane of the tubular epithelial cells. This pumps sodium out of the tubular epithelial cells and potassium into the cell. 2. The other examples include H+‑ATPase, H+‑K+ ATPase, Ca2+‑ATPase, etc. Secondary Active Transport This is the major mechanism by which Na+, glucose and associated solutes are reabsorbed from kidney tubules. The active transport mechanism, i.e. Na+‑K+ ATPase located in the basolateral membrane of epithelial cells pumps Na+ out of the cell. This creates a low concentration of Na+ in the tubular cells. Therefore, Na+ is reabsorbed from the tubular fluid along its concentration gradient into the tubular cells. 1. The carrier protein for Na+ facilitates reabsorption of Na+ into the tubular cells. Glucose is reabsorbed by the same carrier protein that reabsorbs Na+. 2. Therefore, reabsorption of glucose by this mechanism is an example of secondary active transport. 3. The similar mechanism operates in the epithelial cells of intestine. Coupled transport This is a form of facilitated diffusion, serves as major mechanism of transport of solutes in the tubules. There are two mechanisms of coupled transports: symport mechanism, and antiport mechanisms. Symport Mechanism The symport mechanism is the process of coupled transport of two or more solutes in same direction by a carrier protein. The examples are the transport of Na+-glucose, Na+-amino acid, etc. Antiport Mechanism Antiport mechanism is the process of coupled transport of two or more solutes in opposite direction by a carrier protein. An example is the Na+–H+ exchange in the proximal tubule that reabsorbs Na+ from the tubular fluid in exchange for secretion of H+ into it. Concepts in Transport Mechanisms Paracellular Pathway of Transport Close to apical membrane, tubular epithelial cells have tight junctions between them. Immediately after the tight junctions between the epithelial cells, the lateral intercellular space starts. However, these tight junctions are not very tight and they have leaky channels. When transport of solutes and water occurs between the cells through tight junctions and lateral intercellular space, the process is called transport across the paracellular pathway. A considerable quantity of Ca2+ and K+ are reabsorbed in proximal tubule via paracellular pathway. Some amount of Na+ and water is also reabsorbed via this route. This is to differentiate from the transcellular pathway of transport in which transport occurs through the cell. Transport of sodium and glucose from tubular fluid into the tubular cells and from there into the ECF is the example of transport via transcellular pathway Transport Maximum The transport systems in the renal tubule like transport systems in other parts of the body have their maximal rate, which is called as the transport maximum (Tm). 1. This is the rate at which the tubule maximally transports a particular solute. That means, the amount of a particular solute transported depends on the amount of the solute in tubular fluid present up to the Tm for the solute. 2. Tm is the amount of the substance delivered to the tubule per minute. 3. When the concentration of the solute in tubular fluid is more than the Tm concentration, the mechanism of transport is said to be saturated, and beyond this there will be no appreciable increase in transport of the solute. For example, the Tm for glucose is 375 mg/min. in males and 300 mg/min. in females. Tubular Load The quantity of a solute filtered by the glomerulo-capsular filtering barrier and presented to the tubular fluid is the tubular load. Tubular load determines the amount of the substance to be reabsorbed from the tubule, as normally, a constant fraction of the load is reabsorbed by the kidney tubules, which is called glomerulotubular balance. Tubular load also determines the Tm for the substance. The amount of the substance delivered to the tubular fluid per unit time (tubular load of the substance) greatly contributes to the maximum quantity of the substance that can be reabsorbed. However, Tm depends on plasma concentration of the substance and the rate of filtration of the substance, i. e. plasma concentration × GFR. For example, Tm for glucose is 375 mg/min, which indicates that plasma concentration of glucose up to 300 gm%, tubule can transport glucose totally from the tubular fluid (300 mg/100 mL × 125 mL/min). However, normally, glucose appears in urine above 200 mg% (more accurately, above 180 mg% of venous blood) of plasma level. This is because of the mechanism of renal splay for glucose Renal Threshold This is the concentration of the solute in the plasma at or above which the solute first appears in urine or appears in more amount than its normal concentration. For example, normally glucose is not present in urine and its renal threshold is 180 mg% in venous plasma (200 mg% in arterial plasma). Therefore, glycosuria occurs when plasma concentration of glucose is above 180 mg%. Tubular Functions Proximal Tubular Functions The proximal tubule is the most important part of the nephron as it reabsorbs about 67% of the filtered water, Na+, Cl−, K+, and HCO3− and almost all the filtered glucose and amino acids. 1. The proximal tubule has convoluted and straight portions. Though the convoluted part (PCT) comprises 70% of the tubule, functionally both the parts are similar with few minor differences. 2. The primary focus of reabsorption process in the proximal tubule is directed at the Na+ reabsorption, which is usually secondary to electrochemical gradient created by Na+-K+ pump located on the basolateral membrane of the epithelial cells. 3. Reabsorption of water and most of the solutes is directly or indirectly linked with this pump. Therefore, abnormalities of this pump (i. e. Na+ reabsorption process in the tubule) results in many renal dysfunctions. Important Facts: The fluid in the early part of proximal tubule is almost isosmotic to plasma. 1. Na⁺ and its two major anions Cl− and HCO3 − are the major solute in plasma and glomerular filtrate. 2. HCO3− is reabsorbed mainly in the convoluted portion of the proximal tubule leading to its drastic fall in rest of the tubule. 3. Cl− is reabsorbed in the second half of the proximal tubule (later part of convoluted portion and straight portion) which creates a lumen positive transepithelial potential difference that favors passive reabsorption of Na+. 4. About of 67% of filtered K+ is reabsorbed along with 67% of water. 5. Glucose and amino acids are almost completely reabsorbed in proximal tubule resulting in their steep fall in rest of the tubule. 6. Thus, at the end of proximal tubule, only one-third of Na+, Cl− and K+ remain with almost absence of glucose, amino acid and bicarbonate in the tubular fluid. 7. However, urea concentration is increased as it is not at all absorbed in this part of the tubule. Na+ Reabsorption In proximal tubule, reabsorption of Na+ is important among all transport processes as it generates the major driving force for reabsorption of water and other solutes. From tubular fluid, Na+ enters the tubular epithelial cells along the electrochemical gradient. Inside the tubular cells, concentration of Na+ is about 35 meq/L in comparison to about 140 meq/L in the tubular fluid. 1. The lower intracellular concentration of Na+ is due to the activity of Na+‑K+ pump located on the basolateral surface of the cells. Vigorous activity of Na+‑K+ ATPase constantly removes three Na+ out of the cell for bringing in two K+ for each cycle of the pump. This active transport mechanism constantly creates a low concentration of Na+ in the cell. 2. The Na+ removed from the cell into the lateral intercellular space enters interstitial fluid, and the K+ pumped into the cell diffuses out of it through basolateral membrane mostly via K+ channels. 3. Thus, the net effect is the decreased Na+ level in tubular cells. This causes Na+ from tubular fluid to enter the tubular cells. 4. As the Na+ entry from the luminal surface into the cells utilizes the energy generated by Na+-K+ pump on the basolateral surface, the process of Na+ reabsorption is an active transport mechanism. About 67% of filtered Na+ is reabsorbed in proximal tubule. Cotransport and Antiport Mechanisms: From tubular fluid, entry of Na+ into the tubular cells occurs via various cotransport and antiport mechanisms that are located on the apical cell membrane. 1. The carrier protein that transports Na+ also cotransports glucose, amino acids, phosphates, etc. Therefore, reabsorption of these solutes is considered as secondary active transport. 2. Na+ is also transported from tubular fluid by antiport, especially by Na+‑H+ exchanger which reabsorbs Na+ into the cell in exchange for secretion of H+ into the luminal fluid. Normally, Na+‑ H+ exchanger is the primary mechanism of entry of Na+ into the epithelial cells, which accounts for about 60% of the total Na+ entry. Associated Anion Reabsorption: Na+ reabsorption is accompanied by reabsorption of anions, such as HCO3− and Cl− to maintain electroneutrality. However, process of anion absorption along with Na+ is different in first and second half of proximal tubule. In First Half of Proximal Tubule In first half of proximal tubule, Na+ reabsorption is mainly associated with HCO3− and organic solutes like glucose, amino acids, phosphates, etc. 1. Thus, Na+ and HCO3− reabsorption in the first part of PCT is coupled to the transport of organic molecules. 2. Therefore, simultaneous reabsorption of Na+, bicarbonate, and organic solutes from the proximal tubular fluid establishes an osmotic gradient that results in reabsorption of water. In Second Half of Proximal Tubule In second half of proximal tubule, Na+ reabsorption is mainly associated with Cl− reabsorption via transcellular and paracellular pathway. In the later part of proximal tubule, Na+ reabsorption is coupled with the Cl− rather than bicarbonate or organic solutes because of two reasons. 1. In distal part of proximal tubule, concentration of Cl− is very high, whereas the concentration of glucose and amino acid is less in this region as Na+ and bicarbonate are preferentially reabsorbed in the first half of PCT. 2. Also, presence of more chloride-anion antiporter in the distal part of the proximal tubule facilitates transport of Cl− into the cell. Na+ that enters cell is pumped out of it to enter ECF via Na+‑K+ pump located on the basolateral membrane. The Cl− leaves the cell by means of K+-Cl− symporter located on the basolateral membrane. Thus, Na+ and Cl− are reabsorbed from tubular fluid into the interstitial fluid via tubular cells. This is called transcellular pathway of reabsorption of solutes. Increased concentration Na+ in lateral-interstitial space creates an electrical gradient for Cl− ions also to move through the paracellular pathway. This is because the tight junctions between the tubular cells at their apical margin contain leaky channels that transport Cl− along its electrical concentration gradient from the tubular fluid into the interstitial space. This is called paracellular pathway of reabsorption solutes. This paracellular pathway of solute reabsorption constitutes about 25% of NaCl reabsorption in the proximal tubule. Thus, Na+ reabsorption helps in reabsorption of Cl−, HCO3−, other cations and anions and various organic solutes. Transfer of organic and inorganic solutes from tubular fluid into the interstitial space creates the osmotic gradient for the reabsorption of water in the proximal tubule. Water Reabsorption Normally, 65% of the filtered water is reabsorbed in the PCT. 1. The driving force for water reabsorption is the transcellular osmotic gradient, which is established by absorption of Na+ and accompanying solutes. 2. Transcellular and paracellular reabsorption of NaCl and other solutes from tubular fluid into the lateral intercellular and interstitial spaces increases the osmolality of fluid in these spaces. 3. Permeability of epithelium of proximal tubule to water is extremely high. Water passes through the epithelial cells via water channels (aquaporin 1) present in the cell membranes and also through the water channels present in the paracellular route (in tight junctions between the cells). 4. Therefore, even a smaller osmotic gradient (osmolality of interstitial fluid of about 293 mosm/L against osmolality of tubular fluid of about 285 mosm/L) result in adequate movement of water. Thus, water flows along the osmotic gradient via the transcellular and paracellular pathways. 5. Hence, reabsorption of water is coupled with the reabsorption of solutes, especially with that of Na+ and Cl− (as NaCl is osmotically most active). 6. The transfer of large amount (bulk flow) of water helps in transport of ions like K+ and Ca2+ that are carried along with water. This process is called solvent drag. 7. Accumulation of water in the interstitial space increases the hydrostatic pressure that favors transfer of water from there into the ECF. Role of Peritubular Capillaries The peritubular capillaries play and important role in absorption of solutes and water from the tubule. Peritubular capillaries are derived from efferent arteriole and therefore receive blood from the glomerulus. 1. As the blood draining from glomerulus has already been filtered in the glomerular capillary and protein has not been filtered through the filtration barrier in the renal corpuscle, blood in peritubular capillary has high oncotic pressure. 2. Moreover, the hydrostatic pressure is also less in peritubular capillaries as blood has passed through the upstream resistance vessels before entering these capillaries. 3. Thus, high oncotic and low hydrostatic pressures favor uptake of water from the interstitial tissue space surrounding tubules. 4. This transfer of water from peritubular space into peritubular capillaries maintains the gradient for water reabsorption from tubular lumen. Glucose Reabsorption Glucose is reabsorbed completely from tubular fluid in the proximal tubule. 1. It is reabsorbed along with Na+ in the tubule. Na+ is pumped out of th

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