L1 Homeostasis - Albarwani Fall 2024 PDF

L1: Homeostasis  Objectives L1. HOMEOSTASIS 1. Explain the meaning of the term internal environment and homeostasis and appreciate the importance of constancy of the statics (milieu interior). 2. State that homeostasis involves maintaining the internal environment...

L1: Homeostasis  Objectives L1. HOMEOSTASIS 1. Explain the meaning of the term internal environment and homeostasis and appreciate the importance of constancy of the statics (milieu interior). 2. State that homeostasis involves maintaining the internal environment at a constant level (within narrow limits). 3. Explain that homeostasis involves monitoring levels of variables and correcting changes. 4. Understand the components of a feedback system. 5. Contrast the operation of negative and positive feedback mechanisms in control systems with examples. 2  Introduction ▪ Anatomy is the study of body structures and the relationships among them. ▪ Physiology is the study of body functions, including the study of homeostasis (keeping the organ systems of the body in balance). ▪ Pathophysiology is how physiological processes are altered in disease or injury. Structure and function are so closely related (structure mirrors function), e.g. the thin air sacs of the lungs increase surface area to permit movement of gases from the lungs to the blood. The intestinal villi increase surface area for absorption. 3 Levels of organization in the body 1. Chemical: Various atoms and molecules make up the body 2. Cellular: cells are made of molecules. 3. Tissue: consists of similar types of cells. 4. Organ: made up of different types of tissues. 5. Organ system: consists of different organs that work closely together. 6. Organism: made up of the organ systems.  Concept of homeostasis Homeostasis is the maintenance of a steady state in the body’s internal environment despite changes in the external environment. Homeostasis is the core concepts critical to understanding physiology. Regulatory mechanism tend to minimize disturbances to the internal environment. It is a condition of equilibrium (balance) in the body’s internal environment. 5  Homeostasis ▪ The term ‘homeostasis’ is derived from two Greek words: Homeo, which means ‘unchanging’, and Stasis, which means ‘standing’ which means staying the same. ▪ It is a dynamic condition meant to keep body functions in the narrow range compatible with maintaining life. What should stay the same? The internal environment. What is the internal environment? : Is the fluid that surrounds the cells and through which they make life-sustaining exchanges.(mainly the extracellular fluid, interior lilleu). Cellular function depends on the regulation of the composition of the internal environment  Homeostasis and body fluids Claude Bernard wrote: The proper functioning of the cells depends on the precise regulation of the composition of their surrounding fluid. He called the surrounding fluid the internal environment (internal milieu). Claude Bernard 1813-1878 This is the underlying principle of homeostasis. 7  Homeostasis and Body Fluids 1. Intracellular Fluid (ICF): Fluid inside all the cells. 2. Extracellular Fluid (ECF): Fluid outside the cells is composed of: i) Interstitial fluid: ECF between cells. ii) Plasma: ECF within blood vessels. ECF also exists in: Brain and spinal cord → Cerebrospinal fluid (CSF). The lymphatic vessels → Lymph. The joints → Synovial fluid. The eyes → Aqueous humor and vitreous body. 8  Homeostasis and body Fluids Body cells work best if they have the correct: ▪ Volume of extracellular fluid. ▪ Blood volume. ▪ Blood pressure. ▪ Concentration of oxygen and carbon dioxide. ▪ Concentration of nutrients and waste products. ▪ Concentration of electrolytes. ▪ pH of the internal environment. ▪ Etc… Our bodies have mechanisms to keep the cells in a constant internal environment. 9  Homeostatically regulated factors 1. Concentration of nutrients. 2. Concentration of O2 and CO2. 3. Concentration of waste products. 4. pH. 5. Concentrations of water, salt, and other electrolytes. 6. Concentration of hormones 7. Volume and pressure. 8. Temperature. 9. Many other chemicals  Examples of constancy of the internal environment Body core temperature: 370C. Blood pressure: 120/80 mmHg. Arterial Blood: PaO2 100 mmHg; PaCO2 40 mmHg. Blood sugar (glucose): 100 mg/dL (5 mmol/L). Electrolytes: Na+ = 140 mmol/L, K+ = 4 mmol/L. pH: blood pH = 7.4, stomach pH = 2-4 , small intestinal pH = 8 and urine pH = 6. All body cells and systems contribute towards this constancy.  Control of homeostasis ▪ Homeostasis is continually being disturbed by: Physical insults from the external environment such as intense heat or lack of oxygen. Changes in the internal environment such as a drop in blood glucose due to lack of food. Psychological stress such as demands of work or school. ▪ In most cases the disruption of homeostasis is mild and temporary, and the responses of body cells quickly restore balance in the internal environment. ▪ In some cases the disruption of homeostasis is intense and often prolonged → disease (poisoning or severe infections) or death. requires a communication system (NS and endocrine system). 12 Homeostasis is maintained by feedback mechanisms (systems) A feedback system (loop) is a cycle of events in which the state of the body is continually monitored, evaluated and changed. The output of a system “feeds back” to either reverses or strengthen the action taken by the system. 13 Homeostasis is maintained by feedback mechanisms (systems) ▪ A feedback system includes three basic components: Receptor. Control (integrating) center. Effector. ▪ Variable (controlled condition) is a value that changes (e.g. body temperature, blood glucose). ▪ The set point is the normal range of the variable (determined by the control center) that will be optimum for the system to operate (e.g. body temperature around 37°C, blood glucose around 70-100 mg/dL). 14  Components of a feedback system 1. Receptor (sensor): A body structure that monitors changes in a controlled condition (such as body temperature) and sends input to the control center 2. Control center (integrating center): Sets the range of values to be maintained (usually this is done by the brain). The control center evaluates input received from receptors, and compared it to the set point. Then it generates output command (output involves nerve impulses, hormones, or other chemical agents). 3. Effector: The effector receives output from the control center and produces a response or effect that changes the controlled condition (variable) to bring the system back to the set point. Interactions among the components of a homeostatic control system 16  Types of feedback systems I) Negative feedback system: (most control systems) ▪ Opposes an initial change and is widely used to maintain homeostasis ▪ Tends to stabilize a system, correcting the deviation of a variable from the set point. ▪ Example: regulation of BP and regulation of body temperature. II) Positive feedback system: The response amplifies an initial change (strengthens or enforces) the changes in the body’s controlled condition. Tends to disturb the system. Example: Normal childbirth 17 1. Homeostatic regulation of blood pressure  Stimulus: Increase in arterial CO2 or decrease in arterial O2. Receptors: Peripheral Chemoreceptors in aortic and carotid bodies 2. Homeostatic regulation of breathing in response to Control Center: Brain stem changes in O2 and CO2 Effector: Respiratory muscles: breath harder. Outcome: decrease in arterial CO2 or increase in arterial O2. 3. Homeostatic regulation of blood glucose Blood sugar high: Pancreas releases insulin; body cells take in glucose and move it to long-term storage in the liver (glycogen) Blood sugar low: Pancreas releases glucagon; stimulates the liver to break down stored glycogen (into glucose) and release it into the bloodstream 4. Homeostatic regulation of body temperature The hypothalamus detects the temperature of blood as it passes through: Higher than set point→ blood vessels dilate, sweating occurs Lower than set point→ blood vessels constrict, shivering Control of labor contraction during childbirth Positive feedback: causes variables to continue in the same direction as the initial change. Stimulus: Stretch of the uterus. Receptors: Stretch receptors (cervix). Control center: Brain. Effector: Uterine muscles. Delivery of baby will stop the cycle  Feedforward Initiation of responses in anticipation of a change. Feedforward or anticipatory control mechanisms permit the body to predict a change in and initiate a response that can reduce the degree of deviation (change) of a regulated variable out of its normal range. Examples: ▪ Eating increases insulin secretion before glucose enters circulation so reduces large increases in blood glucose ▪ Anticipatory increases in breathing frequency will reduce the time course of the response to exercise-induced hypoxia.  Disruptions in homeostasis can lead to illness and death. It occurs when the fine control of the variable falls outside the normal range. If the control system cannot maintain homeostasis, imbalance occurs. If the imbalance is mild or moderate → disorder or disease occurs. ▪ Disorder: Abnormality of function. ▪ Disease (illness): Characterized by symptoms and signs i) Symptoms: headache, nausea. ii) Signs: fever, high blood pressure, paralysis. If the imbalance is severe → death may result. 24 Body Fluid Compartments and Fluid Balance Lecture 2  Objectives L2: Body Fluid Compartments and Fluid Balance 1. Differentiate between the terms osmole, osmolarity, osmolality, and tonicity. 2. List the typical value and normal range for plasma osmolality. 3. Understand the concepts of osmosis and osmotic pressure. 4. Define tonicity and be able to use the terms isotonic, hypertonic, and hypotonic. 5. Predict the change in transcellular fluid exchange that would be caused by placing a red blood cell in solutions with varying tonicities. 6. State the water content of the body and its physiological variations with age, fat content and gender 7. Know sources of water gain and water loss and understand the distribution of body water in the various body fluid compartments. 8. Understand the role of osmotic pressure and hydrostatic pressure in the distribution of body water into compartments.  % body water is variable ▪ The water content of an individual remains constant over a period of time (kept by homeostasis). ▪ The percentage of body water varies from person to person (mainly due to variability in the amount of their adipose tissue). ▪ Women have lower body water than men. ▪ The percentage of body water decreases progressively with age. ▪ Different tissues have different water content. For examples: ▪ Plasma: >90% water. ▪ Skin, muscle and internal organs: 70-80% 75%-80% of body weight in infant water. ▪ Skeleton (bones): 22% water. 60% of body weight in adult male ▪ Adipose tissue: 10% water. 50-55% of body weight in adult female  Body water is distributed between the ICF Body fluid compartments and the ECF compartments. ▪Intracellular fluid ICF (28 L) ▪Extracellular fluid: ▪Plasma (3 L) 42 L ▪Interstitial fluid, ISF (11 L) 28 L 14 L 11 L  Minor ECF Compartments 1. Lymph: is the fluid being returned from the interstitial fluid to the plasma by means of the lymphatic system, where it is filtered through lymph nodes for immune defense purposes 2. Transcellular fluid small, specialized fluid volumes, secreted by specific cells into a particular body cavity to perform a specialized function. Transcellular fluid includes: ▪ cerebrospinal fluid: surrounding, cushioning, and nourishing the brain and spinal cord. ▪ Intraocular fluid: maintaining the shape of and nourishing the eye ▪ synovial fluid: lubricating and serving as a shock absorber for the joints ▪ pericardial, intrapleural, and peritoneal fluids: lubricating movements of the heart, lungs, and intestines, respectively. ▪ digestive juices: digesting ingested foods. Plasma and interstitial fluid are similar in composition, but ECF and ICF differ markedly. Plasma and Interstitial fluid composition is very similar (except for plasma proteins). Why? Capillary wall is permeable to all ions How fluid moves between different body compartments? Membrane allows water and particles to move between side 1 and side 2 (permeable to both) Start End  Membrane allows only water to move between side 1 and side 2 (not permeable to particles) Solute unable to move from side 2 to side 1 Water moves from side 1 to side 2 by osmosis Water moves from side 1 to side 2 by osmosis Water concentration not equal Solute concentration not equal Tendency of water to diffuse to side 2 is balanced by opposing tendency of hydrostatic pressure difference (column of water) to push water back to side 1. Osmosis of water stops: dynamic equilibrium Osmotic pressure is the pressure applied across the semi-permeable membrane to stop osmosis.  Reabsorption Filtration osmosis  Osmolarity/osmolality To understand osmosis ▪ Is a measure of the total number of dissolved particles in a solution. Osmolarity: is the measure of solute per unit Volume (L) of solvent Osmolality: is the measure of solute per unit Mass (Kg) of solvent ▪ The greater the concentration (Osmolarity) of a solution, the greater the pulling force (Osmotic pressure), and the greater the osmosis ▪ The ionic composition of the ICF fluid is different from that of ECF. ▪ But the Osmolarity of ICF is equal to that of ECF.  Osmosis and osmotic concentrations - Osmosis is the net diffusion of water across a selectively permeable membrane. - Osmosis is the major force responsible for the net movement of water into or out of cells. - Osmosis occurs when there is a difference in osmotic concentration between two compartments - Osmotic concentration is proportional to the number of osmotic particles formed in the solution - Osmotic concentration is measured in Osm/L (osmolarity) = moles x n (n, # of particles in solution). - Normally, cells neither shrink nor swell because ICF and ISF have the same osmolarity - Normal body value is 290 mOsm/L  Osmolarity ▪ Osmolarity is proportional to the number of osmotic particles formed per molecule, once the molecule dissolves. ▪ Osm/L = moles x n (particles of solute/mole in a solution). ▪ Assuming complete dissociation: o 1mole of NaCl will give (1 Na+ + 1 Cl- ) forms a 2 osmolar solution in 1L o 1mole of CaCl2 ( Ca2+ + 2 Cl-) forms a 3 osmolar solution in 1L o 1 mole of glucose forms 1 osmolar solution ▪ Physiological concentrations are in mosm/L 1 mOSM = 10-3 osmoles/L  Semi permeable membrane separate body fluids into compartments Two membranes separate Plasma membrane 1. Plasma (cell) fluid compartments membrane separates ICF ▪ Plasma membrane from surrounding interstitial ▪ Capillary membrane fluid or from plasma movement by osmosis ICF Three compartments: ▪ ICF 2. Capillary membrane ▪ ISF separates plasma from ▪ Plasma surrounding interstitial fluid. Fluid movement by: ECF 1.Hydrostatic pressure (Capillary blood pressure) plasma 2. Colloid osmotic pressure (osmotic pressure due to Capillary membrane protein but not ions). Osmotic pressure at the capillary membrane is called colloid pressure because ions can cross the membrane but protein cannot.  Tonicty ▪ Is the effect the solution has on cell volume—whether the cell remains the same size, swells, or shrinks—when the solution surrounds the cell. ▪ The tonicity of a solution has no units and is a reflection of its concentration of nonpenetrating solutes relative to the cell’s concentration of nonpenetrating solutes ▪ Normal serum (blood) osmolarity = 275-295 mOSM/kg ▪ A solution that has HIGH osmolarity than plasma is called HYPERTONIC solution ▪ A solution that has LOW osmolarity than plasma HYPOTONIC solution ▪ A solution that has EQUAL osmolarity as plasma = ISOTONIC solution  isotonic solution: no volume Fluid movement between change cells and ISF Isotonic fluid gain e.g Intravenous infusion of isotonic Hypertonic solution: water saline (0.9 % NaCl, 5% glucose exit (efflux) cells, cells solution) shrink Neurons dehydration causes Isotonic fluid loss occurs in mental confusion to coma hemorrhage e.g dehydration due to: ▪ Insufficient water intake Hypotonic fluid: cells swell ▪ Excessive water loss Pronounced swelling of brain cells (vomiting or diarrhea) also leads to brain dysfunction. Swelling of muscle cause muscle weakness Expansion of plasma volume may cause hypertension and edema Over hydration due to: - Renal failure with inability to excrete diluted urine - Excessive drinking (transient) - Increase in ADH secretion  Water intoxication The condition of overhydration, hypotonicity, and cellular swelling resulting from excess free water retention (drinking large volume of water is short time)  Water movement across the plasma membrane Water can pass through plasma membrane in 2 ways 2. Through lipid bilayer by 1.Integral membrane proteins simple diffusion. Small amount manages to escape between called aquaporins tails of the lipid (very little)  Water movement between capillaries and ISF Pressure is higher Arteriole Capillary Area of exchange Venule More fluid is filtered at the arteriolar end compared Pressure is lower to venular end. Net fluid movement (is the difference between ▪ Hydrostatic pressure is higher at the arteriolar end of cap hydrostatic and oncotic pressures) is filtration at the and decreases towards the venular end. arterial end and reabsorption at venular end. ▪ Oncotic pressure (also called colloid is the osmotic pressure due to non permeable proteins) remains near the same. Excess fluid is taken back to circulation by lymphatics  Imbalances in fluid movements Due to difference in hydrostatic pressure or oncotic pressure 1. Increase in capillary blood 2. Decrease in the concentration of plasma proteins reduces pressure cause excessive fluid reabsorption. water movement (increased filtration) from plasma to ISF Reduced protein synthesis by causes edema. Poor nutrition the liver (alcoholism) edema Ascites Ascites  Daily water gain and loss Chemical reactions within cells convert food and O2 into energy, producing CO2 and H2O in the process (200-300 ml) Water steady state (water balance) Amount Ingested = Amount Eliminated Water gain per day: 1. Ingestion of liquids and moist foods (2.2-2.3L/day) 2. Metabolic synthesis of water (0.2-0.3L/day) Water loss per day: 1. Insensible water loss by evaporation through skin (0.6L) and exhalation through lungs (0.3 L). 2. Feces (0.1L) 3. Urine (all remaining) Water gain is regulated mainly by drinking through thirst mechanism Rate of formation of metabolic water is not regulated to maintain homeostasis Vasopressin is also called Antidiuretic hormone (ADH)  Regulation of body water loss Kidneys (lecture 13) L3: AUTONOMIC NERVOUS SYSTEM  Lecture Objectives L3. AUTONOMIC NERVOUS SYSTEM 1. Explain the role of the autonomic nervous system in homeostasis. 2. Compare and contrast the autonomic nervous system with somatic system. 3. Describe the components of the autonomic nervous system (autonomic sensory, motor ganglia and plexus neurons 4. Describe that the autonomic sensory neurons is a visceral and mainly involuntary system. 5. Discuss that the autonomic motor neurons is organized into three divisions: sympathetic, parasympathetic and enteric). 6. Describe the neurotransmitters and their receptor in the autonomic sensory neurons. 7. Discuss the physiological effects of the autonomic nervous system. 8. Explain the role of the hypothalamus and other higher brain areas in controlling autonomic functions. General organization of the nervous system The nervous system is organized into: Central nervous system (CNS) consisting of Brain and Spinal cord Peripheral nervous system (PNS) consisting of nerve fibers that carry information between CNS and other parts of the body (periphery). The PNS has afferent division that carries information to the CNS and efferent division that carry information from the CNS  Organization of the peripheral nervous system The afferent division (to the CNS) is divided into: 1. Sensory afferents (body sense) we are aware of - Somatic afferents: arising from body surface (from skin, muscle etc). - Special senses (vision, hearing, taste, smell) 2. Viscera afferents (for subconscious information derived from internal viscera (stomach, bladder, uterus, blood vessel, blood pressures etc) The efferent division (from CNS) is divided into: 1. Somatic nervous system (SNS, voluntary) which contains motor fibers that innervate skeletal muscle 2. Autonomic nervous system (ANS, involuntary) which contains fibers that innervate smooth and cardiac muscles and glands  Autonomic Nervous System (ANS) ▪ ANS is the involuntary subdivision of the peripheral nervous system that regulates body activities that are generally not under conscious control. ▪ ANS is the portion of the nervous system that controls most visceral functions of the body. ▪ ANS consists of motor neurons that innervate smooth and cardiac muscles and glands ▪ ANS helps to control arterial pressure, gastrointestinal motility, gastrointestinal secretion, urinary bladder emptying, sweating, body temperature, and many other activities. ▪ ANS is under control of CNS centers in brain stem and spinal cord, hypothalamus, and cerebral cortex. ▪ Hypothalamus is the main integrative center of ANS activity.  An autonomic nerve pathway consists of a two-neuron chain In total, there are: ▪ 12 pairs of cranial (brain) nerves and ▪ 31 pairs of spinal nerves: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral 1 coccygeal nerves Two-neuron chain The cell body of the first neuron is located in the CNS. Its axon (preganglionic fiber) synapses with the cell body of the second neuron, which lies within a ganglion. The axon of the second neuron (postganglionic fiber), innervates the effector organ. Comparison between autonomic and somatic nervous systems Compare ANS with somatic NS ANS 1. Location of cell bodies 2. Myelination 3. Number of neurons involved 4. Effector organs Somatic NS  Anatomical differences between ANS divisions Sympathetic: (thoracolumbar) Parasympathetic (craniosacral) ▪ Cranial nerves: III, VII, IX, and X (X= vagus ▪ T1-T12, nerve accounts for ~ 90% of all parasympathetic ▪ L1-L3 fibers) ▪ Sacral S2, S3 and S4  Anatomical differences between ANS divisions Parasympathetic Sympathetic Three main differences between sympathetic and parasympathetic divisions: Eye Eye Brain stem 1. Sites of origin: Salivary Skin Parasympathetic craniosacral; glands Cranial Sympathetic thoracolumbar; Sympathetic Salivary ganglia glands Heart 2. Relative lengths of fibers: 1 Fibers originate 1 Fibers originate ▪ Parasympathetic has long Lungs in the brain stem (cranial fibers) or in the thoracic and lumbar spinal cord. Lungs T1 preganglionic and short sacral spinal cord. Heart postganglionic fibers. 2a Preganglionic 2a Preganglionic fibers are long. fibers are short. Stomach ▪ Sympathetic has short Stomach 2b Postganglionic 2b Postganglionic Pancreas preganglionic and long fibers are short. fibers are long. Liver postganglionic fibers. Pancreas and gall- 3 3 Ganglia are L1 Ganglia are bladder within or near close to spinal cord. 3. Location of ganglia: Liver and visceral effector organs. Adrenal gland ▪ Parasympathetic ganglia are gall- bladder located in or near the their visceral effector organ. Bladder Sacral Bladder ▪ Sympathetic ganglia lie close to Genitals Genitals spinal cord. The ANS controls involuntary visceral organs Most visceral organs are innervated by both sympathetic and parasympathetic fibers (with few exceptions). This results in dynamic antagonisms that precisely control visceral activity Sympathetic fibers increase heart and respiratory rates, and inhibit digestion and elimination Parasympathetic fibers decrease heart and respiratory rates, and allow for digestion and the discarding of wastes  ANS Neurotransmitters Preganglionic neurons: ▪ Sympathetic and parasympathetic neurons release acetylcholine (ACh) which binds to nicotinic receptors ▪ Sympathetic nerves to the adrenal medulla stimulate the release of adrenaline into circulation Post ganglionic neurons Sympathetic postganglionic to all organs release nor- epinephrine (nor- adrenaline), which binds to adrenergic receptors Sympathetic nerves to sweat glands release ACh Parasympathetic to all organs release ACh binds to muscarinic receptors  Physiological characteristic of ANS Sympathetic dominance Parasympathetic dominance ▪ Mobilization & increased metabolism “flight or fright” ▪ Routine maintenance “rest &digest” “fight or flight” ▪ It dominates during D activities – Digestion, ▪ It dominates during E activities – Exercise, Defecation, and Diuresis Excitement, Emergency, and Embarrassment ▪ Also called: SLUDD (Salivation Lacrimation Urination Digestion Defecation) Sympathetic dominance Fight-or-flight response. ▪ ↑ production of ATP. ▪ Dilation of the pupils. ▪ ↑ heart rate and blood pressure. ▪ Dilation of the airways. ▪ Constriction of blood vessels that supply the kidneys and gastrointestinal tract. ▪ ↑ blood supply to the skeletal muscles, cardiac muscle, liver, and adipose tissue ▪ ↑ glycogenolysis ↑ blood glucose, ↑ lipolysis. E “Situation” Exercise, Emergency, Excitement and Embarrassment  Parasympathetic dominance Rest-and-digest responses D “Situation” Digest, Defecate, Diuresis. Conserve and restore body energy ↑ digestive and urinary function ↓ body functions that support physical activity SLUDD (Salivation Lacrimation Urination Digestion Defecation)  Cholinergic receptors Two types of cholinergic receptors, named after drugs that bind to them and mimic ACh effects, nicotine and muscarine (mushroom poison). 1. Nicotinic receptors: two subtypes: a. Nn: found on all postganglionic neurons (sympathetic and parasympathetic) in autonomic ganglia and hormone-producing cells of the adrenal medulla. b. Nm: found on the sarcolemma of skeletal muscle cells at neuromuscular junctions. The effect of Ach on nicotinic receptors is always stimulatory. 2. Muscarinic receptors: three subtypes (M1-M3). – Found on all effector cells stimulated by postganglionic cholinergic fibers. – The effect of ACh on muscarinic receptors can be either inhibitory or excitatory, depending on the receptor type of the target organ. – Example: Binding of ACh to cardiac muscle cells slows heart rate, whereas binding to intestinal smooth muscle cells increases motility.  Adrenergic receptors Two major classes that respond to NE or epinephrine: – Alpha () receptors: ▪ Divided into two subclasses: (1 Virtually all tissue), 2 (neurons, pancreas) – Beta () receptors: ▪ Divided into three subclasses: 1 (cardiac muscle), 2 (other tissue), 3 (adipose tissue). ▪ Effects depend on which subclass of receptor predominates on the target organ. ▪ Example: NE binding to cardiac muscle 1 receptors causes increase in rate, whereas epinephrine binding to 2 receptors on bronchial tissue causes bronchial relaxation.  Localized versus diffuse effects ▪ Parasympathetic division tends to elicit short-lived and highly localized control over effectors. – ACh is quickly destroyed by acetylcholinesterase. ▪ Sympathetic division tends to be longer-lasting with body-wide effects: – NE is inactivated more slowly than ACh. – NE and epinephrine hormones from adrenal medulla have prolonged effects that last even after sympathetic signals stop (circulate in blood and taken up and degraded by the liver).  Autonomic tone Is the balance between sympathetic and parasympathetic activity Most organs receive both sympathetic and parasympathetic innervation Autonomic tone is regulated by the hypothalamus; it increases one division and reduces the other. Few structures receive only sympathetic such: ✓ kidney, ✓ sweat glands, ✓ blood vessel, ✓ adrenal medulla.  Non-cholinergic non adrenergic ANS neurotransmitters Some autonomic fibers are non-adrenergic and non-cholinergic. They do not release either NE or ACh. They use other chemical mediators as neurotransmitters Example: ▪ Adenosine triphosphate (ATP) is secreted by some sympathetic fibers supplying blood-vessel smooth muscle to cause vasoconstriction ▪ Nitric Oxide (NO) released by parasympathetic fibers supplying the blood vessels of the penis contributes to the vasodilation that leads to erection (hardening of the penis). Many autonomic fibers release cotransmitters along with the classical neurotransmitters. For example, certain sympathetic postganglionic fibers cosecrete neuropeptide Y (NPY) along with NE. NPY functions as a neuromodulator; that is, it modulates the release and actions of NE instead of exerting a direct action on the effector organ.  Patterns of ANS innervation ▪ Antagonism: In most organs the effects of the two divisions are antagonistic ▪ Cooperative effects are seen when the two divisions act on different effectors to produce a unified effect. ▪ Parasympathetic fibers cause vasodilation and are responsible for erection of the penis and clitoris ▪ Sympathetic fibers cause ejaculation of semen in males and reflex peristalsis in females  Sympathetic tone Almost all blood vessel smooth muscle is entirely innervated by sympathetic fibers only, so this division controls blood pressure, even at rest. Sympathetic tone (vasomotor tone): A continual state of partial constriction of blood vessels. ▪ If blood pressure drops, sympathetic fibers fire faster than normal to increase constriction of blood vessels and cause blood pressure to rise. ▪ If blood pressure rises, sympathetic fibers fire less than normal, causing less constriction (dilation) of vessels, which leads to a decrease in blood pressure. ▪ This tone allows the sympathetic system to shunt blood where needed.  Parasympathetic tone ▪ Parasympathetic division normally dominates heart and smooth muscle of the digestive and urinary tract organs, and it activates most glands except for adrenal and sweat glands. – Slows the heart and dictates normal activity levels of digestive and urinary tracts. – These organs also exhibit parasympathetic tone where they are always slightly activated. ▪ The sympathetic division can override these effects during times of stress. Properties of the cardiac muscle L4 Objectives L4. CARDIAC MUSCLE AND CARDIAC CONDUCTION SYSTEM Describe the functional organization of the cardiovascular system Describe the structural and functional characteristics of cardiac muscle tissue and its conduction system. Define the terms: Rhythmicity, Excitability, Conductivity and Contractility. Describe cardiac syncytium. Outline the normal pathway of the cardiac impulse. Compare and contrast action potential in sinoatrial node and ventricular muscle. Explain the significance of the plateau and refractory period in ventricular muscle action potential. The functional organization of the cardiovascular system The heart, its chambers, walls and valves The myocardium ▪ Exhibit branching ▪ Adjacent cardiac cells are joined end to end by intercalated discs ▪ The intercalated discs contain desmosomes, which hold the fibers together, and gap junctions, which allow muscle action potentials to conduct from one muscle fiber to its neighbors. ▪ Gap junctions allow the entire myocardium of the atria or the ventricles to contract as a single, coordinated unit (syncytium). ▪ Atrial syncytium (2 atria contract together) and ventricular syncytium (2 ventricles contract together)  Properties of the cardiac muscle 1. Autorhythmicity: The ability to initiate a heart beat continuously and regularly without external stimulation 2. Conductivity: The ability to conduct excitation through the cardiac tissue 3. Excitability: The ability to respond to a stimulus of adequate strength and duration (i.e. threshold or more) by generating a propagated action potential 4. Contractility: The ability to contract in response to stimulation  Autorhythmicity and the conduction system The ability of the heart to initiate it’s beat continuously and regularly without external stimulation Autorhythmicity is - myogenic (independent of nerve supply) - is due to the presence of specialized excitatory & conductive system of the heart  The cardiac muscle Two specialized types of cardiac muscle cells 1. Contractile cells ◼ 99% of cardiac muscle cells ◼ Contract ◼ Normally do not initiate own electricity (action potentials) 2. Autorhythmic cells ◼ 1% of cardiac muscle cells ◼ Do not contract ◼ Act as a pacemaker (set the rhythm of electrical excitation) ◼ Form the conductive system (network of specialized cardiac muscle fibers that provide a path for each cycle of cardiac excitation to progress through the heart) ◼ Specialized for initiating and conducting action potentials responsible for contraction of working cells  Locations of autorhythmic cells 1.Sinoatrial node (SA node) Specialized region in the right atrial wall near opening of superior vena cava. 2. Atrioventricular node (AV node) Small bundle of specialized cardiac cells located at base of right atrium near septum 3. Bundle of His (atrioventricular bundle) Cells originate at AV node and enters interventricular septum Divides to form right and left bundle branches (4) which travel down the septum, curve around tip of ventricular chambers, travel back toward atria along outer walls 5. Purkinje fibers Small, terminal fibers that extend from right and left bundle of His and spread throughout the ventricular myocardium  Pacemaker potentials in autorhythmic fibers ▪ The autorhythmic cells do not have a stable resting membrane potential. Rather, they repeatedly depolarize to threshold spontaneously. ▪ The spontaneous depolarization is a pacemaker potential. When it reaches threshold, it triggers an action potential. ▪ On their own, autorhythmic fibers in the SA node would initiate an action potential every 0.6 sec., or 100 times/min. ▪ This rate is faster than that of any other autorhythmic fibers. 10  Why sinoatrial node is a pacemaker Non-SA nodal tissues are latent pacemakers that can take over (at a slower rate), should the normal pacemaker (SA node )fail But normal SA node fires at 100/min so how come HR is 70/min) ?  Heart rate is determined primarily by autonomic influences on the SA node. Effect of Parasympathetic stimulation on the Heart ▪ ACh binds to the SA node muscarinic receptors as a result it increases K+ permeability of the SA node and so decreases HR. Effect of Sympathetic stimulation on the Heart ▪ NE binds to adrenergic receptors and speeds up the rate of depolarization as a result of greater inward movement of Na+ and Ca2+ and increases HR  Conductivity Property by which excitation is conducted through the cardiac tissue  Depolarization: inside the cell is less -ve Tissue Conduction rate (meter/s) Atrial 0.3 muscle Atrial 1 pathways AV node 0.05 (slowest) Bundle of 1 His Purkinje 4 (fastest) system Ventricular 0.3-0.5 muscle  Spread of cardiac excitation Cardiac impulse originates at the SA node Action potential spreads throughout right and left atria Impulse passes from atria into ventricles through AV node (only point of electrical contact between atria and ventricles) Action potential is briefly delayed at AV node (ensures atrial contraction precedes ventricular contraction to allow complete ventricular filling) Impulse travels rapidly down interventricular septum by means of bundle of His Impulse rapidly disperses throughout myocardium by means of Purkinje fibers Rest of ventricular cells are activated by cell-to-cell spread of impulse through gap junctions  Electrocardiogram The ECG is a record of the overall spread of electrical activity through the heart. As action potentials propagate through the heart, they generate electrical currents that can be detected at the surface of the body. ▪ By comparing tracings from different leads with one another and with normal records it is possible to (1) determine if the conducting pathway is abnormal, (2) if the heart is enlarged, (3) if certain regions of the heart are damaged, and (4) the cause of chest pain.  Electrocardiogram (ECG) ▪ As action potentials propagate through the heart, they generate electrical currents that can be detected at the surface of the body. ▪ Three recognizable deflections with each heartbeat: P : wave represents atrial depolarization. QRS complex : represents ventricular depolarization. T wave: represents ventricular repolarization. 17  3) The AP propagates rapidly again 2) After P wave begins, the atria 1) Cardiac action potential arises in after entering the AV bundle. contract (atrial systole). SA node. It propagates Depolarization progresses down throughout the atrial muscle and the septum, upward to give→ down the AV node. Conduction of AP slows at the QRS complex. AV node because fibers there Atrial repolarization occurs at the have small diameter and fewer As the atrial contractile fibers same time but it is masked by the gap junctions → 0.1 sec delay depolarize, the P wave appears larger QRS complex. that gives the atria time to in the ECG. 18 contract. 4) Contraction of ventricular contractile 5) Repolarization of ventricular fibers (ventricular systole) occurs contractile fibers begins at 6) Shortly after the T wave begins, shortly after the QRS complex the apex and spreads the ventricles start to relax appears and continues during the throughout the ventricular (ventricular diastole). ST segment. myocardium. By 0.6 sec, ventricular This produces the T wave in repolarization is complete and the ECG about 0.4 sec after ventricular contractile fibers the onset of the P wave. are relaxed. 19 20  Cardiac action potentials Ventricular muscle action potential ▪ Action potential initiated by the SA node travels along the conduction system and spreads out to excite the “working” atrial and ventricular muscle fibers called contractile fibers. ▪ An action potential occurs in contractile muscle fibers as follows: 1. Depolarization. 2. Plateau. 3. Repolarization. 21  Cardiac muscle has long refractory period ▪ Period of time during which another Skeletal muscle Cardiac muscle contraction cannot be triggered ▪ Long refractory period (200-300 msec) compared to skeletal muscle (1-5 msec) Plateau phase ▪ During this period membrane is refractory (cannot be stimulated) to further stimulation until contraction is over. ▪ It lasts longer than muscle contraction, prevents tetanus (continuous contraction) short refractory period ▪ Gives time to heart to relax after each contraction, prevent fatigue A long refractory period ▪ It allows time for the heart chambers to fill during diastole before next prevents tetanus of cardiac contraction muscle.  Cardiac muscle are excited by action potential (coming all the way from SA node Cardiac muscle plasma membrane depolarizes Calcium enters the muscle Contraction  Summary Normal function of the specialized excitatory and conductive system of the heart results in: atria contract before ventricles allow filling of the ventricles all portions of ventricles to contract simultaneously effective pressure generation within the ventricle Introduction to the cardiac cycle and cardiac output L5  Objectives 1. L5. INTRODUCTION TO CARDIAC CYCLE AND CARDIAC OUTPUT 2. Explain the ECG waves and correlate them with mechanical events. 3. Define heart rate, stroke volume, venous return, and cardiac output. 4. Describe the phases of the cardiac cycle. 5. Identify the origin of heart sounds. 6. Describe the flow of blood through the chambers of the heart and through the systemic and pulmonary circulations. 7. Explain the Starling’s law of the heart. 8. List the function of the autonomic nervous system on the heart.  The cardiac cycle All cardiac events associated with one heartbeat ▪ The cardiac cycle consists of alternate periods of systole (contraction and emptying) and diastole (relaxation and filling). ▪ Contraction results from the spread of excitation across the heart, whereas relaxation follows the subsequent repolarization of the cardiac muscle. ▪ The atria and ventricles go through separate cycles of systole and diastole.  Phases of the cardiac cycle When the heart rate is 75 beats/min, a cardiac cycle lasts 0.8 sec. It can be divided into three main phases: 1. Atrial systole (lasts for 0.1 sec): The atria are contracting but the ventricles are relaxed. 2. Ventricular systole (lasts for 0.3 sec): The ventricles are contracting but the atria relaxed in atrial diastole. 3. Relaxation period (lasts for 0.4 sec): both atria and ventricles are relaxed. N.B.: The faster the heart beats, the shorter the relaxation period, whereas the durations of atrial systole and ventricular systole shorten only slightly.  Cardiac cycle ▪ One cardiac cycle (CC) includes all events associated with one heartbeat. Composed of: ▪ Systole: contraction and emptying ▪ Diastole: relaxation and filling ▪ Contraction occurs as a result of the spread of depolarization, while relaxation occurs as a result of repolarization. ▪ At a heart rate of 75 beats /min, the cardiac cycle lasts 0.8 secs (60 sec/75 beats) ▪ In each CC, atria & ventricles alternatively contract & relax ▪ Cardia cycle describes events associated with: ▪ ECG, ▪ pressure changes ▪ volume changes ▪ valve activity and ▪ heart sounds  Recall from lecture 4 Green= depolarization Red= repolarization 2 Atria-ventricular valves Tricuspid (right) and Bicuspid (left also called mitral valve) 2 Semilunar valves; Pulmonary valve (from RV to pulmonary artery) and aortic valve (from LF to aorta)  Important terminologies ◼ Venous return: Blood that returns to the heart/ min (= CO) ◼ End diastolic volume (EDV): blood in the ventricles at the end of diastole. ◼ Preload: the degree of stretch on the heart before it contracts. ◼ End systolic volume (ESV): blood that remains in the blood at the end of systole ◼ Ejection fraction: fraction of EDV that is ejected (%), used to measure heart efficiency ◼ Afterload: the pressure that must be exceeded before ejection of blood from the ventricles can occur. ◼ Stroke volume: is the amount of blood pumped out of each ventricle during a single beat (about 70 ml). It can be expressed as : SV = EDV ̶ ESV  Bottle = heart Stroke V: volume of blood ejected by each ventricle Afterload: the pressure that Venous return: Blood during each contraction must be exceeded before that returns to the heart/ ejection of blood from the min (= CO) ventricles can occur. End diastolic volume Preload: the End systolic volume (EDV):blood in the ventricle contractility (ESV): blood that degree of stretch at the end of diastole (before of the ventricle remains in the ventricle contraction) before it contracts at the end of systole  QRS :ventricular depolarization P wave: Atrial T wave: ventricular depolarization repolarization Atria Atria relax Both atria and contract Ventricles contract ventricles relaxed  Events during the cardiac cycle: ventricular volumes 70% of blood enters the ventricles before atrial contraction Wigger’s diagram  Heart sounds ◼ Auscultation: act of listening to sounds within the body, usually done with a stethoscope ◼ Sound of heartbeat comes primarily from blood turbulence caused by closing of heart valves ◼ 4 heart sounds in each cardiac cycle – only 2 are loud enough to be heard in a normal heart (S1 and S2) ◼ Lubb – AV valves close ◼ Dupp – SL valves close Events during cardiac cycle; heart sounds First heard sound (S1) lubb: Louder & longer than second. Caused by closure of A-V valves (soon after beginning of ventricular systole). Second heart sound (S2) dupp: shorter & not as loud as first Caused by closure of semilunar valves (beginning of ventricular diastole). Events during the cardiac cycle: pressures  Events during cardiac cycle Passive filling during Atria contraction empties The A-V valves close ventricular and atrial more blood into ventricles. (semilunar still closed) the diastole The total volume of blood is ventricles start to contract (this the end diastolic volume period when the ventricles A-V valves open (EDV). start to contract while all the Semilunar valves valves are closed is called close At this time the semilunar isovolumetric contraction valves are closed. (i.e contraction while volume is the same)  Events during cardiac cycle (cont) ▪ The pressure within the contracting ▪ The semilunar valves (aortic and ventricles open the semilunar pulmonary) close and the ventricle valves (aortic and pulmonary) and relax. At this time the A-V valves blood is ejected from the ventricles are still close so this phase is (ventricular systole). called isovolumetric relaxation. ▪ The volume remaining in the ventricles at the end of contraction is ▪ The A-V valves open and the called end systolic volume (ESV). ventricles start to fill (ventricular filling), then atria contract Left-ventricular pressure-volume loop for a single cardiac cycle.  Cardiac output (CO) CO is the volume of blood ejected from the left ventricle (or the right ventricle) into the aorta (or pulmonary trunk) each minute. CO equals the stroke volume (SV) multiplied by heart rate (HR) CO = SV X HR Ho we regulate CO? SV: volume of blood ejected by each ventricle during each contraction HR: number of heart beats per minute. In a typical resting male: CO = SV X HR = 70 ml X 75/minute = 5.25 L/min Cardiac reserve: difference between maximum CO and CO at rest ▪ Average cardiac reserve 4-5 times resting value. ▪ Athletes may reach 7-8 times. ▪ Heart failure patients may have little or no cardiac reserve.  Regulation of stroke volume ◼ A healthy heart will pump out the blood that entered its chambers during the previous diastole. ◼ At rest stroke volume is about 50-60% of EDV. ◼ Three factors regulate SV: I. Preload: The degree of stretch on the heart before it contracts. Proportion to EDV II. Cardiac contractility III. Afterload: The pressure that must be exceeded before ejection of blood from the ventricles can occur.  I. Preload: effect of stretching ▪ Is the degree of stretch on the heart before it contracts. ▪ Greater preload increases the force of contraction. This is known as Frank-Starling law of the heart. ▪ Frank-Starling law of the heart: the more the heart fills with blood during diastole, the greater the force of contraction during systole (within limits). ▪ Preload is proportional to end- diastolic volume (EDV).  1. Preload: effect of stretching (con.) Two factors determine EDV: 1. Venous return (volume of blood flowing back to the heart through systemic veins). The more the venous return the more the EDV (the more the preload) 2. Duration of ventricular diastole (HR) Because ventricular filling occurs during diastole very rapid heart rate (tachycardia) shortens diastole duration causing reduced ventricular filling and therefore reduced EDV  II. Contractility Strength of contraction at any given preload. The more the ventricles contract, the more the stroke volume ◼ +ve inotropism:  contractility ▪ Sympathetic stimulation ▪ Hormones; adrenaline and noradrenaline ◼ -ve inotropism:  contractility ▪ inhibition of the sympathetic system ▪ anoxia ▪ acidosis What about parasympathetic activity?  III. Afterload ▪ Pressure in pulmonary tract is a bout 20 mmHg and in the aorta is about 80 mm Hg. ▪ This pressure must be overcomed before the semilunar valves open (pulmonary and aortic valves). ▪ Afterload depends on: Afterload ▪ Elasticity of large arteries ▪ Peripheral resistance of arterioles ▪ An  in afterload →  SV → more blood remains in ventricle at end of systole (ESV) ▪ Conditions that  afterload include: Hypertension Narrowing of arteries by atherosclerosis  Regulation of heart rate Several factors, the most important are: 1. Nervous factors :sympathetic  parasympathetic  HR 2. Chemical factors adrenaline, thyroid hormone: HR 3. Other factors affecting HR: ▪ Age: Newborn HR ~120 beats/min Old people may also develop  HR ▪ Gender: Adult females have higher HR than males ▪ Exercise: Athletes have bradycardia (60 bpm or under) (more efficient heart) ▪ Body temperature (BT): BT (fever or exercise) → HR BT→  HR & contractility Autonomic regulation of heart rate Summary of regulation of cardiac output Hemodynamics of Blood Flow L6  Objectives HEMODYNAMICS OF BLOOD FLOW 1. Describe the main function of the arteries, capillaries and veins. 2. Compare and contrast the systemic and pulmonary circulation. 3. Explain the factors that affect the blood flow. 4. Describe the relationship between pressure, flow and resistance in the vasculature. 5. Define resistance and the factors that determine resistance. 6. Understand the effects of adding resistance in series vs.in parallel in total resistance and flow. 7. Describe the change in pressure along vascular tree and explain how flow to any organ is altered by change in resistance to that organ. 8. Define venous return and factors that affect it.  Functions of Blood Vessels ▪ Arteries Carry blood away from heart to tissues. ▪ Arterioles ▪ Smaller branches of arteries. ▪ Capillaries ▪ Smaller branches of arterioles. ▪ Smallest of vessels across which all exchanges are made with surrounding cells. ▪ Venules ▪ Formed when capillaries rejoin. ▪ Return blood to heart. ▪ Veins ▪ Formed when venules merge ▪ Return blood to heart Blood flow from the heart  Elastic arteries ▪ Largest arteries. ▪ Also known as conducting arteries – conduct blood to medium-sized arteries. ▪ Function as pressure reservoir. ▪ Help propel blood forward while ventricles relaxing.  Systemic and pulmonary circulations Systemic circuit (high pressure, high resistance): Left side of the heart. Receives blood from lungs. Ejects blood into the aorta. Systemic arteries, arterioles. Gas and nutrient exchange in systemic capillaries. Systemic venules and veins lead back to the right atrium. Systemic blood vessel walls dilate in response to low O2 to increase O2 delivery. Pulmonary circuit (low pressure, low resistance): Right side of the heart. Receives blood from systemic circulation. Ejects blood into the pulmonary trunk and then pulmonary arteries. Gas exchange in pulmonary capillaries. Pulmonary veins take blood to the left atrium. Pulmonary blood vessels constrict under low O2 to ensure most blood flows to better-ventilated areas of lung  Systemic veins ▪ low-resistance passageways to return blood from the tissues to the heart ▪ Serve as a blood reservoir. Because of their storage capacity to store blood. ▪ Called capacitance vessels  Hemodynamics of blood flow Blood flow is the volume of blood that flows through any tissue in a given period of time (in mL/min). Total blood flow is the cardiac output (CO) ▪ Volume of blood that circulates through systemic (or pulmonary) blood vessels each minute. Distribution of CO depends on: 1. Pressure differences that drive blood through tissue. ▪ Flows from regions of higher pressure to regions of lower pressure. ▪ The greater the pressure difference the greater the blood flow. 2. Resistance to blood flow in specific blood vessels. ▪ Higher resistance means smaller blood flow.  Relations of pressure, flow and resistance ▪ Flow (volume/time) = difference in pressure (P) (mmHg) / resistance (R). ▪ Directly proportional to the pressure gradient. ▪ Inversely proportional to resistance.  1) Blood Pressure Blood pressure (BP) is the hydrostatic pressure exerted by blood on the walls of blood vessels. Contraction of the ventricles generates BP. BP is determined by: 1) Cardiac output (CO) [CO = HR × SV]. 2) Blood Volume (BV). 3) Vascular resistance [R]. ▪ Systolic BP: highest pressure attained in arteries during ventricular systole. ▪ Diastolic BP: lowest arterial pressure during ventricular diastole.  Blood Flow = ΔP /R Cardiac Output = Mean Arterial Pressure / Total Peripheral Resistance CO = MAP/TPR This means that if the CO increases then MAP will also increase as long resistance remains unchanged CO: Cardiac Output, MAP: mean arterial pressure TPR: total peripheral resistance (resistance in the circulation)  Pressure gradient in the systemic circulation ΔP = MAP - 0 mmHg = MAP MAP: mean arterial pressure  Mean arterial pressure ▪ Mean arterial pressure (MAP) is the average blood pressure in arteries. ▪ MAP can be estimated as follows: MAP = diastolic BP + 1/3 pulse pressure). MAP = Cardiac Output (CO) × Resistance (R). ▪ Blood pressure also depends on the volume of blood. ▪ Normal blood volume is about 5 Liters. ▪ Reduction in blood volume, like (hemorrhage) may reduce blood pressure if the volume loss ▪ If cardiac output rises due to an increase in SV is more than 10%. or HR (CO = SV x HR), then MAP will also ▪ Increases in blood volume (water retention in increase as long as resistance remains steady. the body) may increase blood pressure.  CO = ΔP /R R = resistance R1 P = Pressure A P1 P2 R2 B P3 P4 Blood flow in A = Blood flow in B Blood vessel  Most vascular resistance is in arterioles As blood leaves the aorta and flows through the systemic circulation, its pressure falls progressively Flow = Pressure difference/Resistance F= ΔP/R If the flow is the same in all vascular segments (=CO) Then a drop in pressure means an increase in Resistance Most drop in pressure occurs in small arteries and arterioles. This means most resistance is in the Most of the pressure small arteries and arterioles drop  2) Vascular resistance ▪ Resistance is a measure of opposition of blood flow through a vessel. ▪ Resistance arises due to: o interactions between the moving fluid and the stationary tube wall. o interactions between molecules in the fluid (viscosity). ▪ The higher the R, the smaller the flow. Flow  1/R ▪ Factors determining the vascular resistance are: 1. Blood vessel radius. 2. Blood viscosity. 3. Vessel length.  Factors determining vascular resistance Vascular resistance depends on: 1. Size of the lumen: resistance is inversely proportional to the diameter. Vasoconstriction makes the lumen smaller. The smaller the diameter, the larger the resistance). ▪ The resistance to flow is inversely proportional to the fourth power of the radius: R  1/d4 ▪ The smaller the diameter the greater the resistance. ▪ If the diameter  by ½, the resistance  16 times). Therefore, vessel radius is the major determinant of resistance to blood flow (occurs mainly in arterioles due to vasoconstriction and vasodilatation) and is the main factor regulated by the body.  Factors determining vascular resistance 2. Blood viscosity (thickness): resistance is directly proportional to the viscosity. ▪ Blood viscosity depends mostly on the ratio of RBCs to plasma volume and, to a smaller extent, on the concentration of plasma proteins in plasma. ▪ Higher viscosity means higher resistance. Any condition that increases viscosity like dehydration or polycythemia (high number of RBCs will increase R → ↑ BP. ▪ A decrease in RBCs or plasma protein will reduce R → ↓ BP. 3. Total blood vessel length: resistance is directly proportional to the vessel’s length; the longer the blood vessel, the greater the resistance (e.g., obesity).  Total peripheral resistance ▪ Systemic vascular resistance (SVR), also called Total Peripheral Resistance (TPR), refers to all vascular resistances offered by systemic blood vessels. ▪ Control of the TPR is a major function of arterioles (by changing their diameter). ▪ Slight vasodilation or vasoconstriction have a large effect on SVR. Total peripheral resistance is mainly determined by arteriolar vasoconstriction and vasodilation ▪ Arteriolar smooth muscle normally displays a state of partial constriction (vascular tone). ▪ Vascular tone due to: - myogenic activity. - sympathetic activity. ▪ Basic vascular tone can be influenced by a variety of factors (hormones, O2 CO2 temperature et) which change in resistance to flow Some organs are in series and other in parallel A: Resistance in series Rtotal = R1 + R2 + R3…. B: Resistance in parallel 1/Rtotal = 1/R1 + 1/R2 + 1/R3…  Venous return ▪ Venous return is the volume of blood flowing back to the heart through systemic veins. ▪ Occurs due to pressure generated by contractions of the left ventricle. ▪ A small pressure difference from the venules (16 mm Hg) to the right atrium (0 mm Hg) is sufficient to cause venous return to the heart. ▪ If the pressure increases in the right atrium or ventricle, venous return will decrease. ▪ Beside the heart, two other mechanisms pump blood from the lower body to the heart: 1. Skeletal muscle pump: due to muscle contraction. 2. Respiratory pump: due to breathing. Both depend on the presence of one-way valves in the large veins.  Skeletal Muscle Pump Skeletal muscle pump – milks blood in one direction due to the presence of valves. It operates as follows: 1) While standing, both venous valves (proximal and distal; one-way valves) Proximal valve are open, and blood flows upward toward the heart. Distal valve 2) Contraction of leg muscle compresses the veins → Push blood through the proximal valve (milking) and the distal valve closes. 3) After muscle relaxation, pressure drops and causes the proximal valve to close. The distal valve opens because the pressure in the foot is higher than in the leg and the veins fill with blood from the foot.  Respiratory Pump It is based on alternating compression and decompression of veins due to inspiration and expiration. During inspiration, the diaphragm moves downward, thoracic cavity pressure is reduced and abdominal cavity pressure increases → abdominal veins are compressed moving blood from abdominal veins to thoracic veins and then into the right atrium. During expiration, the pressure reverses, the valves in the veins prevent backflow of blood from the thoracic veins to the abdominal veins. Summary  Regulation of Local Blood Flow and Capillary Exchange L7  Objectives REGULATION OF LOCAL BLOOD FLOW AND CAPILLARY EXCHANGE 1. Define autoregulation of blood flow and distinguish between short-term and long-term autoregulatory responses. 2. Discuss the three main mechanisms for control of local blood flow and contrast their relative dominance in the coronary, splanchnic, renal, cutaneous, and skeletal muscle vascular beds. 3. Describe the movement of water, gases, solutes and macromolecules across capillary membranes. 4. With the aid of a figure describe briefly the Starling’s forces involved in capillary exchange. 5. Mention the role of lymphatics in the removal of fluid from interstitial space. 6. Define the term edema and explain how it occurs on the basis of Starling’s forces. 7. Explain how edema can occur when capillary permeability increases and give an example. 2  Recall from lecture 6 ▪ Large arteries are pressure reservoirs because they distend and recoil. ▪ Small arteries and arterioles are resistance arteries because they constrict and dilate, decreasing or increasing flow to the tissue. ▪ Capillaries are the site of exchange. ▪ Large veins are blood reservoirs because they expand and store the volume of blood (capacitance vessels). 3  Regulation of local blood flow ▪ Blood pressure is regulated independently of local blood flow control or cardiac output control ▪ % cardiac output delivered to each organ depends on the demand of the blood flow of the organ at a specific time. (not fixed) ▪ Because blood is delivered to all organs at the same MAP, blood flow to a specific organ is controlled by changing the resistance (arteriolar diameter) in that organ only (Flow = ΔP/R) ▪ Changes in arteriolar diameter within an organ change its resistance, and so the local blood flow ▪ Only the blood supply to the brain remains remarkably constant no matter ▪ Vasoconstriction in one organ will not change TPR but what the person is doing will reduce blood flow to that organ. 4 Two categories: Local (intrinsic) controls are changes within an organ that adjust blood flow by affecting the smooth muscle of the organ’s arterioles to alter their caliber and resistance. It is much stronger and can override the external control 1. Acute control: A result of rapid vasoconstriction or dilatation of arterioles caused by: ▪ Metabolic changes (O2, CO2, K+, H+), histamine release. ▪ Local physical influences include how much the vessel is stretched and the local application of heat or cold. 2. Long-term control: slow changes in flow (within days, weeks, or months). ▪ A result of  or  in size & number of blood vessels. Extrinsic control of arteriolar diameter is mainly done by sympathetic NS and hormones (angiotensin II and ADH) and is used to alter blood pressure and not local blood flow. 5 Acute response: Local metabolic influences on arteriolar radius help match blood flow with the organ’s needs. Metabolic response. Acute control of local blood flow with changes in pressure F = ΔP /R R increased Pressure autoregulation: very little increase in blood flow with an increase in blood pressure. 7  Autoregulation of organ blood Flow ▪ The ability of a tissue to automatically adjust its blood flow to match its metabolic demands is called autoregulation. ▪ Mechanisms of autoregulation are: 1. Metabolic response:  in blood flow, when metabolism increases. Local metabolites (O2, CO2, H+, K+, Adenosine – etc → vasodilation). 2. Myogenic response: Also called pressure autoregulation: Smooth muscle cell contracts when stretched this is important to prevent tissue damage when pressure increases. 8  Short term regulation of local blood flow Neural: The resistance vessels of nearly every organ are innervated with fibers of the sympathetic nervous system. Stimulation of α-adrenergic receptors causes vasoconstriction, while stimulation of β- β-adrenergic receptors causes vasodilatation (present is coronary and skeletal muscle circulation). Myogenic: Increased pressure and the accompanying stretch of vascular smooth muscle cells (VSMCs) elicit vasoconstriction, whereas decreased pressure elicits vasodilation. Metabolic regulation: Small arteries are sensitive to local metabolic needs of the organs. The following cause vasodilatation: ▪ Decrease O2, ▪ Increase CO2, H+, K+, osmolarity, adenosine Endothelial Mechanisms: Endothelial cells release a variety of vasoactive substances such as nitric oxide (NO), which relaxes VSMCs and prevents leukocyte adhesion and endothelin which is a vasoconstrictor. Each mechanism may have more influence in one circulation than the other 9  Mechanisms of longterm alteration of tissue blood flow collaterals Angiogenesis: Growth of new blood vessels. Collateral circulation: Angiogenic factors are released from : When an artery or a vein is blocked a new ▪ Ischemic tissue. vascular channel may develop around the ▪ Rapid growing tissue (cancer). blocked area and allows partial resupply of ▪ Tissue with excessively high metabolism. blood flow, e.g. collateral blood vessels after 10 thrombosis of one of the coronary arteries.  Blood flow through special circulations ▪ Cerebral circulation (brain) ▪ Coronary circulation (heart) ▪ Gastrointestinal (splanchnic) ▪ Renal (kidneys) ▪ Skeletal muscle ▪ Cutaneous circulation (skin) 11  Cerebral circulation ▪ The brain accounts for only ∼2% of the body’s weight, yet it receives ∼15% of the resting cardiac output. ▪ Of all the tissues in the body, the brain is the least tolerant of ischemia. Distribution of blood within the brain is controlled by local metabolic factors. An important metabolic regulator is PCO2, increasing of which causes cerebral Blood flow from one area of the vasodilatation. brain may be increased when the specific area is active but the total Excellent flow autoregulation: An increase in blood blood flow remains almost pressure causes vasoconstriction (myogenic constant autoregulation), so it reduces the cerebral flow and hence protects the brain. Influenced relatively little by the autonomic nervous system.  Coronary circulation ▪ The coronary circulation receives 5% of the resting cardiac output ▪ Sympathetic nerves cause the heart to beat more frequently (+ve chronotropic effect) and more forcefully (+ve inotropic effect), the increased mechanical work of the myocardium leads to coronary vasodilation through metabolic pathways more than the effect of sympathetic on vascular beta receptors. ▪ Myocardial blood flow parallels myocardial metabolism, the harder the heart beats the more the coronary blood flow. Important regulator is adenosine is released when: o metabolic activity of the heart increases. o coronary blood flow in insufficient o fall in myocardial PO2. ▪ Adenosine then causes vasodilation and increases coronary blood flow. ▪ During systole, vessels within the cardiac muscle wall are compressed; therefore, coronary flow occurs mainly during diastole.  Skeletal muscle blood flow Skeletal muscle blood flow accounts for about 20% of cardiac output. During extreme physical exertion, more than 80% of cardiac output can be directed to contracting muscles. Metabolites released by active muscle trigger vasodilation and an increase in blood flow. Blood flow is strongly determined by local regulatory (tissue and endothelial) factors such as tissue hypoxia, adenosine, K+, CO2, H+, and nitric oxide. 14  Skeletal muscle ▪ Norepinephrine from sympathetic nerves bind α1 adrenergic receptors on skeletal arterioles, causing vasoconstriction. ▪ Adrenal medulla, upon stimulation by the sympathetic nervous system, releases Norepinephrine and Epinephrine (more abundant) ▪ Epinephrine combines with both α1 and β2 receptors but has a much greater affinity for β2 receptors. ▪ Activation of β2 receptors produces vasodilation, ▪ But not all tissues have β2 receptors; they are most abundant in the arterioles of the skeletal muscles and the heart. ▪ During sympathetic discharge, the released epinephrine combines with the β2 receptors in the skeletal muscle (also the heart) to cause vasodilatation.. ▪ Also, During exercise, the local regulatory mechanisms override the sympathetic influences  Gastrointestinal blood Flow ▪ Two capillary beds partially in series with each other; blood from the capillaries of the GI tract, spleen, and pancreas flows via the portal vein to the liver. In addition, the liver receives a separate arterial blood supply. ▪ Sympathetic activation causes vasoconstriction, mediated by α-adrenergic receptors, in reflex response to decreased arterial pressure and during stress. ▪ Blood flow to the gastrointestinal tract increases up to eight-fold after a meal (postprandial hyperemia) due to: ▪ release several hormones from the GI system itself some of which are vasoactive. ▪ Consumption of more O2 and production of vasodilatory metabolites (e.g., adenosine and CO2). ▪ Increase in the activity of parasympathetic which indirectly dilates blood vessels (by increasing metabolites). Sympathetic activity directly constricts splanchnic vessels. 16  Cutaneous circulation (Skin) ▪ Sympathetic activity (more important than all other factors). ▪ Local metabolites: Effect is poor. ▪ At room temperature, skin arterioles are already under the influence of a moderate rate of sympathetic discharge (sympathetic tone). ▪ An appropriate stimulus—cold, fear, or loss of blood, for example— causes reflex enhancement of this sympathetic discharge, and the arterioles constrict further. ▪ In contrast, an increased body temperature reflexively inhibits sympathetic input to the skin, the arterioles dilate to radiate body heat. 17  Renal circulation (kidneys) ▪ The kidneys comprise less than 0.5% of total body weight. However, they receive ∼20% of the cardiac output. ▪ This high blood flow provides the blood plasma necessary for forming an ultrafiltrate in the glomeruli and eventually urine formation. ▪ Pressure autoregulation is the most important factor determining renal blood flow. ▪ Sympathetic stimulation causes vasoconstriction, mediated by α- adrenergic receptors, in reflex response to decreased arterial pressure and during stress. ▪ Angiotensin II is also a major vasoconstrictor. These reflexes help conserve sodium and water.  Transport across the capillary wall ▪ It is the ultimate goal of the circulation. ▪ 7% of blood at any time is present in the systemic capillaries. ▪ Three different types: 1.Continuous: Endothelial cells form a continuous tube except for intercellular clefts. Eg in brain and lungs. 2.Fenestrated: The plasma membrane has fenestrations or pores, e.g. kidneys, villi of small intestine. 3.Sinusoidal: Have large fenestrations and an incomplete basement membrane → Protein & RBCs can pass. 19  Transport across capillary wall The mission of the entire cardiovascular system is to keep blood flowing through capillaries to allow capillary exchange, the movement of substances between blood and interstitial fluid. Substances enter and leave capillaries by three basic mechanisms: 1. Simple diffusion. 2. Transcytosis. 3. Bulk flow: Filtration and Reabsorption. 20  Transport across capillary wall 1. Diffusion : Most important method of capillary exchange is simple diffusion (down the gradient). O2 and nutrients from blood to interstitial fluid to body cells. CO2 and wastes released by body cells move from interstitial fluid to blood. 2. Transcytosis: ▪ Substances in blood plasma become enclosed within tiny pinocytotic vesicles that first enter endothelial cells by endocytosis, then move across the cell and exit on the other side by exocytosis. ▪ Important mainly for large, lipid-insoluble molecules that cannot cross capillary walls in any other way. 21 3. Bulk Flow: filtration and reabsorption ▪ Passive process in which large numbers of ions, molecules, or particles in a fluid move together in the same direction. The substances move at rates far greater than can be accounted for by simple diffusion. ▪ Based on the pressure gradient, bulk flow occurs from an area of higher pressure to an area of lower pressure and continues as long as a pressure difference exists. ▪ Diffusion is more important for solute exchange between blood and interstitial fluid, but bulk flow is more important for the regulation of the relative volumes of blood and interstitial fluid. Filtration: Pressure-driven movement of fluid and solutes from blood capillaries into interstitial fluid. Reabsorption: Pressure-driven movement of fluid and solutes from interstitial fluid into blood capillaries. 22  Forces influencing bulk flow Interstitial fluid Blood Colloid Blood Hydrostatic Osmotic Pressure Pressure Capillary Interstitial Fluid Interstitial Fluid Hydrostatic Pressure Osmotic Pressure Interstitial fluid 23 Forces influencing fluid movement (bulk flow) across the capillary wall 1. Blood Hydrostatic Pressure: Is the hydrostatic pressure exerted on the inside of the capillary by the blood. Generated by pumping action of heart (about 37 mm Hg at arteriolar end and 17 mm Hg at venous end). Pushes fluid out of the capillaries into interstitial fluid. 2. Interstitial fluid osmotic pressure Due to very small amount of protein present, if any, in the interstitial fluid (0 mm Hg). Pulls fluid out of the capillaries into the interstitial spaces. 3. Blood Colloid Osmotic Pressure Due to plasma proteins (about 25 mm Hg). Pulls fluid from interstitial spaces back into the capillaries. 4. Interstitial fluid hydrostatic pressure Fluid pressure exerted on the outside of the capillary by the interstitial fluid (0-1 mmHg). Pushes fluid back into the capillaries. 24  Pressures promoting filtration and reabsorption 3L/day Filtration of 20L of fluid/day. Reabsorption of 17L fluid/day The lymphatic system Functions of the lymphatic system: 1. Route for returning excess filtered fluid. 2. Defense against disease as lymph nodes contain phagocytes. 3. Transport of absorbed fat from the digestive tract. 4. Return of filtered protein.  Edema ▪ Edema is an abnormal increase in interstitial fluid volume. ▪ It occurs when filtration greatly exceeds reabsorption. ▪ It can results from either: 1. Excess filtration. 2. Inadequate reabsorption. 3. Reduced return of excess fluid by lymphatics. 27  Edema Two situations may cause excess filtration: The situation for reduced return of excess fluid by lymphatics: 1. Increased capillary blood pressure → ▪ Removal of lymphatic drainage more fluid to be filtered. channels (e.g., mastectomy). ▪ Blockage of lymphatics with filariasis 2. Increased permeability of capillaries → : (elephantiasis). Some plasma proteins escape to interstitial fluid → , which raises interstitial fluid ▪ Blockage of lymph nodes with cancer. osmotic pressure (can be caused by ▪ Congenital absence of/or abnormality chemicals, bacteria, thermal, or mechanical of lymph vessels. agents). One situation commonly causes inadequate elephantiasis reabsorption: ▪ Decreased concentration of plasma proteins → decreases the blood colloid osmotic pressure (inadequate synthesis or dietary intake or loss of plasma proteins). 28 Regulation of blood pressure L8  Objectives REGULATION OF BLOOD PRESSURE 1. Define the terms: systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and pulse pressure and the term total peripheral resistance. 2. List the short and long-term mechanisms involved in blood pressure regulation. 3. Describe the role of baroreceptors on blood pressure regulation 4. Describe how hormones regulate blood pressure  Arterial blood pressures ▪ Arterial B