Smooth Muscle HHP Fall 2024 PDF

CELLULAR PHYSIOLOGY Smooth Muscle J. H. Alcon, MD [email protected] 1  LEARNING OBJECTIVES 1. Contrast characteristics of single unit and multi unit smooth muscle. 2. Describe the molecul...

CELLULAR PHYSIOLOGY Smooth Muscle J. H. Alcon, MD [email protected] 1  LEARNING OBJECTIVES 1. Contrast characteristics of single unit and multi unit smooth muscle. 2. Describe the molecular structure of smooth muscle fiber. 3. Describe the mechanism of smooth muscle contraction and relaxation. 4. Describe the role of calcium - calmodulin and ATP in muscle contraction. 5. List the differences between skeletal muscle, cardiac and smooth muscle cells. 2  SMOOTH MUSCLE o Not organized in sarcomeres - there are no striations but there are thick and thin filaments o Functions: ✓ Motility Ex: To propel chyme along the GIT or to propel urine along the ureter ✓ Maintain tension: Ex: Smooth muscle in the walls of blood vessels and airways maintain radius 3  STRUCTURE OF SMOOTH MUSCLE o Dense bodies or plasma membrane: functionally similar to Z-lines anchor the thin filaments o Diagonally arranged thick and thin filaments: contract via sliding filament mechanism o No striations: thick and thin filaments are not organized or regularly aligned o Ca2+ dependent cross-bridge movements between actin and myosin filaments generate force o Some of the membrane-dense bodies of adjacent cells Smooth muscle cells can contract as much as 80% of their are bonded together by intercellular protein bridges: length instead of being limited to less than 30%, as occurs force of contraction is transmitted from one cell to the in skeletal muscle next 4  STRUCTURE OF SMOOTH MUSCLE: CAVEOLAE o Small invaginations of the cell membrane that abut the surfaces of sarcoplasmic reticulum (SR) o Suggest a rudimentary analog of the transverse tubule system of skeletal muscle o Action potentials transmitted into the caveolae excite Ca2+ release from the abutting SR in the same way that action potentials in skeletal muscle transverse tubules cause release of Ca2+ from the skeletal muscle longitudinal SR o In general, the more extensive the sarcoplasmic reticulum in the smooth muscle fiber, the more rapidly it contracts.  INNERVATION: AUTONOMIC NERVOUS SYSTEM o No specialized nerve-muscle junction o Autonomic neurons form synapses with groups of cells, not individual cells o Neurotransmitter is released at varicosities (swellings) found along the length of the axon so neighboring groups of cells will contract together o Gap junctions between cells allow electrical signals to spread from one cell to another INNERVATION: HORMONES  TYPES OF SMOOTH MUSCLE o Smooth muscles are classified depending on whether the cells are electrically coupled: 1. Multiunit smooth muscle - has little or no coupling between cells 2. Single Unit or Unitary smooth muscle has gap junctions between cells: faster spread of electrical activity throughout the organ and coordinated contraction 3. Combination of unitary and multiunit smooth muscle 8  SINGLE-UNIT OR UNITARY SMOOTH MUSCLE o Functions as a syncytium: electrical stimulation of one cell is followed by stimulation of adjacent smooth muscle cells o Sparse innervation: fewer neurons innervate groups of smooth muscle cells connected by gap junctions o Myogenic: contracts regularly without input from a motor neuron 9  SINGLE-UNIT OR UNITARY SMOOTH MUSCLE o Visceral (single-unit) smooth muscle is present in: - Gastrointestinal tract - Ureter - Bladder - Uterus o Gap junctions permit electrical coupling between cells because they are low-resistance pathways for current flow ✓ Ex. APs occur simultaneously in the smooth muscles of the bladder  contraction and emptying of entire organ occur at once VSMC = vascular smooth muscle cell ✓ Gap junctions facilitate contraction of smooth muscle in a coordinated fashion 10 UNITARY SMOOTH MUSCLE: SLOW WAVE POTENTIALS OR PACEMAKER WAVES o Unitary smooth muscle are characterized by spontaneous pacemaker activity, or slow waves o Slow Wave Potentials: unstable RMPs that continuously cycle through depolarization and repolarization phases o Frequency of slow waves sets a characteristic pattern of APs within an organ that determine the frequency of contractions 11 UNITARY SMOOTH MUSCLE: SLOW WAVE POTENTIALS OR PACEMAKER WAVES o Not every cycle reaches depolarization threshold and thus an AP will not always fire o Cell membrane depolarization will periodically reach depolarization threshold and an AP will fire  triggering contraction of the myocytes o Clinical correlation: bowel sounds are Slow wave normally irregular on auscultation (5-30/min) because slow waves do not regularly reach threshold to produce an AP therefore contractions of the small intestines are very irregular 12  ACTION POTENTIALS IN UNITARY SMOOTH MUSCLE o Action potentials occur in unitary smooth muscle in the same way that they occur in skeletal muscle o They do not normally occur in most multi-unit types of smooth muscle o The action potentials of visceral smooth muscle occur in one of two forms: 1) spike potentials 2) action potentials with plateaus. 13  1) SPIKE POTENTIALS o Typical spike action potentials occur in most types of unitary smooth muscle o The duration of this type of action potential is 10 to 50 milliseconds o Such action potentials can be elicited in many ways: ▪ electrical stimulation ▪ action of hormones on the smooth muscle ▪ action of neurotransmitter substances ▪ stretching the muscle ▪ spontaneous generation in the muscle fiber Recorded from smooth muscle of the intestinal wall. itself (slow waves) 14  2) ACTION POTENTIALS WITH PLATEAUS o The onset of this action potential is similar to that of the typical spike potential o The repolarization is delayed for several hundred to as much as 1000 milliseconds (1 second) instead of rapid repolarization of the muscle fiber membrane o The plateau accounts for prolonged contraction that occurs in the ureter, uterus under some conditions, and certain types of vascular smooth muscle o Ex: uterine contractions during labor Recorded from a smooth muscle fiber of the uterus This is the type of action potential also seen in cardiac muscle fibers that have a prolonged period of contraction 15  MULTIUNIT SMOOTH MUSCLE o Each smooth muscle cell acts mostly independently: often is innervated by a single nerve ending, as occurs for skeletal muscle o covered by a thin layer of basement membrane–like substance, a mixture of fine collagen and glycoprotein that helps insulate the separate fibers from one another o Less gap junctions between cells o Found in places where fine control of contraction is needed 16 ORGANS WITH MULTIUNIT SMOOTH MUSCLE o Multiunit Smooth Muscle is present in: Ciliary Muscle Iris Muscle Tracheal Muscle Bronchial Muscle Larger Blood Vessels Vas Deferens  ELECTRICAL CHARACTERISTICS: MULTIUNIT SMOOTH MUSCLE o Neurogenic: neural regulation through the ANS is important o Stable RMP: few voltage-gated channels o Graded potentials: typically do not display action potentials when stimulated to contract, only local potentials develop 18  MULTIUNIT SMOOTH MUSCLE USES GRADED POTENTIALS o Their cell membrane has only a few voltage-gated channels that can cause action potentials o Junctional potentials: graded depolarization in response to neurotransmitters which cause the graded contraction response Graded changes in Em (membrane potential) are common in multiunit smooth muscles (e.g., vascular), where action potentials are not generated and propagated from cell to cell. F = force generated Example: iris of the eye 19  Local Tissue Factors and Hormones Can Cause Smooth Muscle Contraction Without Action Potentials Approximately half of all smooth muscle contraction are in vascular smooth muscle Smooth muscle in arterioles, meta-arterioles, and precapillary sphincters respond rapidly to changes in: (1) local tissue chemical factors (2) various hormones (3) stretch caused by changes in blood pressure Specific factors that can relax the vessel wall for increased blood flow through powerful local feedback control: 1. Lack of oxygen in the local tissues causes smooth muscle relaxation and vasodilation 2. Excess carbon dioxide causes vasodilation In the normal resting state, many of 3. Increased hydrogen ion concentration causes vasodilation these small blood vessels remain slightly 4. Others: adenosine, lactic acid, potassium ions, nitric oxide, and contracted = blood vessel tone increased body temperature  Myogenic Response Autoregulation: maintains blood flow to tissues such as the brain at a relatively constant flow over a wide range of blood pressures Myogenic response maintains autoregulation through: o Vasoconstriction in response to an increase in distending pressure (stretch) in an artery o Vasodilation in response to a decrease in transmural pressure (over a given range of pressures) Example: distention of a resistance artery results in an immediate elevation of intracellular Ca2+, followed by vasoconstriction in an effort to maintain relatively constant flow The mechanism underlying this elevation of intracellular Ca2+ and subsequent vasoconstriction is complex  SMOOTH MUSCLE ACTIVITY PATTERNS o Phasic smooth muscle: exhibiting rhythmic or intermittent activity includes smooth muscles in the walls of the gastrointestinal (GI) and urogenital tracts corresponds to the single-unit category o Tonic smooth muscle continuously active Includes vascular smooth muscle, respiratory smooth muscle, and some sphincters continuous partial activation of tonic smooth muscle is not associated with action potentials, although it is proportional to membrane potential. correspond to the multiunit smooth muscle 22  EXCITATION-CONTRACTION COUPLING IN SMOOTH MUSCLE o Mechanism differs from that of striated muscle Ca2+ channels open much more slowly than o Smooth muscle cell membrane has far more Na+ channels and also remain open longer. voltage-gated Ca2+ channels than skeletal muscle but few voltage-gated Na+ channels o Flow of Ca2+ to the interior of the fiber is mainly responsible for the action potential o Smooth muscle: has no troponin ✓ Calmodulin controls the interaction of actin and myosin by the binding of Ca2+ to another protein, MLCK: Myosin Light Chain Kinase ✓ Ca2+-calmodulin regulates myosin-light-chain kinase (MLCK) and therefore regulates cross- bridge cycling 23  MECHANISM OF SMOOTH MUSCLE CONTRACTION 1. Intracellular Ca2+ concentration increases when Ca2+ enters the cell through calcium channels in the cell membrane or is released from the sarcoplasmic reticulum 2. Ca2+ binds to calmodulin (CaM) to form a Ca2+-CaM complex, which then activates myosin light chain kinase (MLCK) 3. Active MLCK phosphorylates the myosin light chain 4. Myosin head attaches with the actin filament and smooth muscle contracts 24  MECHANISM OF SMOOTH MUSCLE RELAXATION 1. Ca2+ concentration decreases below a critical level as Ca2+ is pumped out of the cell or into the sarcoplasmic reticulum 2. Ca2+ is then released from calmodulin (CaM) 3. Myosin phosphatase removes phosphate from the myosin light chain 4. Myosin head detaches from the actin filament and smooth muscle relaxes 25 CALCIUM IN EXCITATION CONTRACTION COUPLING o Most of the Ca2+ that causes contraction enters the muscle cell from the extracellular fluid at the time of the action potential or other stimulus o The sarcoplasmic reticulum is only slightly developed in most smooth muscle unlike that in skeletal muscle o Latent period before contraction begins: rapid diffusion of Ca2+ into the cell from the ECF when the calcium channels open = 200 to 300 milliseconds *This latent period is about 50 times as long Store-operated Ca2+ channel for smooth muscle as for skeletal muscle near junctional SR contraction. 26  EXCITATION-CONTRACTION COUPLING IN SMOOTH MUSCLE 27  Regulation of smooth muscle myosin interactions with actin by Ca2+-stimulated phosphorylation 1 Relaxed state: cross-bridges are present as a high- energy myosin-ADP-Pi complex in the presence of ATP Ca2+-calmodulin–dependent myosin light-chain kinase (MLCK) phosphorylates the cross-bridge that enables attachment of myosin to actin Phosphorylated cross-bridges cycle until they are dephosphorylated by myosin phosphatase Cross-bridge phosphorylation at a specific site on a 2 myosin regulatory light chain requires ATP in addition to that used in each cyclic interaction with actin 28  SMOOTH MUSCLE ACTIVITY PATTERNS o Phasic contraction: myoplasmic Ca2, cross-bridge phosphorylation, and force reach a peak and then return to baseline o Tonic contraction: myoplasmic Ca2+ and cross- bridge phosphorylation decline after an initial spike but do not return to baseline levels During this later phase, force slowly increases and is sustained at a high level but maintained with only 20% to 30% of the cross-bridges phosphorylated, and thus ATP sustained force of contraction utilization is reduced “latch state”: condition of tonic contraction during which force is maintained at low energy expenditure. 29  LATCH MECHANISM IN SMOOTH MUSCLE o The latch state occurs when myosin is dephosphorylated by myosin phosphatase o Actin-myosin complex that has dephosphorylated light chains stay in a locked position because of their very low affinity for ATP o Contraction can be maintained without further ATP hydrolysis and thus without further energy expenditure o Organs such as the intestines, urinary bladder, gallbladder, and Binding of a ligand to the sarcolemma results in elevation of free intracellular Ca2+ through either other viscera often maintain depolarization of the cell membrane and opening of Ca2+ channels or activation of the enzyme phospholipase C tonic muscle contraction almost indefinitely at low ATP cost 30  STRESS-RELAXATION OF SMOOTH MUSCLE o Ability of visceral unitary type of smooth muscle of many hollow organs to return to nearly its original force of contraction seconds or minutes after it has been elongated or shortened (stretched) Example: Urinary bladder o Stress-relaxation: sudden increase in fluid volume in the urinary bladder stretches the smooth muscle in the bladder wall → immediate large increase in pressure in the bladder → pressure returns almost exactly back to the original level after 15-60 secs - when the volume is increased by another step, the same effect occurs again Allows a hollow organ to maintain about the same amount of pressure inside its lumen o Reverse stress-relaxation: when the volume is suddenly despite sustained large changes in volume decreased → the pressure falls drastically at first but then rises in another few seconds or minutes to or near the original level 31 Comparison of Muscle Structure and Function 32  Review Question 1 Relaxation in smooth muscle occurs when: A. Myosin kinase attaches phosphate to the myosin head B. Calcium bind to calmodulin C. Myosin phosphatase removes phosphate from myosin D. Calcium channels open E. Calcium is released from the sarcoplasmic reticulum 33  Review Question 2 A physiologist is researching characteristics of both smooth muscle and skeletal muscle. Unlike skeletal muscle, the contraction of smooth muscle requires which of the following? A. Activation of ryanodine receptors B. Phosphorylation of myosin light chains C. Presence of intracellular calcium D. Troponin binding of calcium E. Voltage activation of dyhydropyridine receptors 34  Review Question 3 Tension development in smooth muscle is controlled by various factors that are not important for regulation of skeletal muscle contraction. Which of the following factors are important for initiating smooth muscle contractions? Hormones Paracrines Autonomic Nervous System A No No No B No No Yes C Yes No Yes D Yes Yes No E Yes Yes Yes 35  Answers 1. C 2. B 3. E 36  helpful reading material Guyton and Hall Textbook of Medical Physiology, John E. Hall PhD and Michael E. Hall MD, MS, 14th ed, chapter 8, pp 101-109. Berne & Levy Physiology, Bruce M. Koeppen, MD, PhD, 8th ed, chapter 14, pp. 277-297. 37 End…. 39