Smooth muscle function 2023-4 - Tagged.pdf

Faculty of Life Sciences and Medicine Dr Greg Physiology & Anatomy of Systems (4MBBS102/4MBBS1B1) Knock (after PI Aaronson) Fundamentals of Physiology & Pharmacology block Dpt. Of Physiology Smooth Muscle Function ...

Faculty of Life Sciences and Medicine Dr Greg Physiology & Anatomy of Systems (4MBBS102/4MBBS1B1) Knock (after PI Aaronson) Fundamentals of Physiology & Pharmacology block Dpt. Of Physiology Smooth Muscle Function  Lecture teaching objectives 1.List the organs containing smooth muscle and describe the role of SM in the functioning of each of these organs 2.Describe the structure of smooth muscle-containing tissues, particularly arteries 3.Compare the structure of SM cells to that of striated muscle cells 4.Describe the cellular mechanisms by which smooth muscle cells contract in response to activation of G q- coupled receptors 5.Describe the mechanisms by which smooth muscle cells relax in response to nitric oxide and the activation of Gs coupled receptors. 6.Explain how membrane depolarisation promotes contractility either as a steady state modulation of E m, by firing of action potentials or as a combination of both (depending on smooth muscle type) Human Physiology: 7.Contrast An Integrated the regulation Approach of the crossbridge (8in cycle Ed); Chapter 12.3 th SM to that of striated muscle  Smooth muscle summary Location: Walls of hollow organs, including blood vessels (except for capillaries!) Function of smooth muscle containing organs: to act as the body’s conduits for the transport of gases, liquids and solids Morphology: Cells not striated (thus ‘smooth’), worm-shaped Regulation: By the autonomic nervous system (ANS) By hormones and locally released substances In the GI tract, rhythmic contractions are initiated by pacemaker cells  Smooth muscle-containing organs Iris and ciliary body: Control Fallopian tube: Mediates movement of eggs from pupil diameter and focussing ovaries to uterus of the lens Uterus (myometrium): Labour and parturition Vas deferens: Delivery of sperm for ejaculation  Smooth muscle-containing organs Bladder (detrusor), Gastrointestinal tract: Respiratory system: ureters, urethra: urine mixing and propulsion of GI Controls diameter of storage and micturition contents airways  Smooth muscle-containing organs: Blood vessels Large artery Large vein Low resistance, Low resistance, high conducting vessels capacitance vessels Several elastic Few elastic layers layers Lumen Endothelium Endothelium Vena cava Aorta Wide lumen Many smooth Few smooth muscle layers muscle layers Venule Arteriole Capacitance Main resistance vessels, vessels control regional blood flow Capillary Smooth Endothelium Endothelium (no smooth muscle) muscle cells Lumen Lumen Connective Lumen tissue Endothelium Vascular smooth muscle cell structure Dense bodies Sarcoplasmic reticulum (stores Ca2+) Intermediate filaments contraction Actin Myosin Structural features of SMCsshape, Lack of striations. Elongated Dense bodies (D) anchor actin filaments. Like cardiac Z-lines, composed of a actinin. Endoplasmic/sarcoplasmic reticulum (ER) stores Ca2+ (arrows). D Gap junctions (G) between cells through which current and small molecules can flow from one cells to another D G Higher ratio of actin to myosin compared to striated muscle D 1.0 µm  How is the contraction of smooth muscle regulated? Smooth muscle type Main stimuli Action potentials? Vascular ANS Autacoids released by the vascular Definitions endothelium or from tissue around the blood vessel Sometimes Hormones and other blood-borne Autacoid (also called local hormones): substances physiologically active factors released by nearby cells acting in an autocrine or Airways ANS, mainly PNS and adrenaline paracrine manner (PCRS block) Autacoids No ANS: autonomic nervous system – a branch Intestinal Interstitial cells of Cajal of the nervous system that controls the (PGRS block) ANS (SNS, PNS, enteric) activity of the heart, visceral organs, blood Endocrine hormones Yes Autacoids vessels and glands Myometrium Intrinsic rhythmicity (stage 2) ANS Prostaglandins (autacoids) & Yes oxytocin (pituitary hormone) Bladder ANS (ANS lecture) Autacoids from the urothelium Yes  Regulation of striated muscle Skeletal muscle (3rd Nov) Cardiac muscle (14th Nov) Ach release from motor AP from SA node is conducted into the myocardium Skeletal: neurons AP frequency myocytes depolarised by neighbouring cells brief depolarisation Force (EPP) opening of voltage-gated Na+ channels opening of voltage-gated Na+ channels myocytes fire APs muscle fibres fire APs RyR = ryanodine receptor opening of voltage-gated Ca2+ channels in T-tubule, voltage-gated Ca2+ channel activates RyR on the SR ↑ Ca2+ between T tubule and SR Ca2+ release from SR Ca2+ release from SR via RyR Cardiac: SNS activity ↑ cytoplasmic Ca2+ ↑ cytoplasmic Ca 2+ And/or stretch muscle fibre twitch Force brief myocyte contraction gulation of smooth muscle contraction is more complex (varie blood vessels ANS airways autocoids, hormones ↑ opening of pressure ↑ stretch receptor- gated channels IP3 membrane opening of voltage- Ca2+ Ca2+ release from Ca2+ Pacemaker cells ↑ depolarisation gated Ca2+ channels influx SR sensitisation GI Tract ↑ cytoplasmic ANS Intrinsic oscillations in Ca2+ ↑ autocoids membrane potential hormones myometrium detrusor relatively sustained contraction  A typical muscular artery blood vessel sympathetic nerve collagen fibroblast tunica adventitia smooth tunica muscle cells media tunica intima gap junctions internal elastic lamina endothelial cells Vascular tone is the result of a balance between constricting and dilating influences Adventitia Tissue metabolites Smooth muscle Endothelium Direct action on the Blood-borne NO is a vasodilator smooth muscle is hormones Thus, actions on the usually pro-contractile (Adrenaline, endothelium are angiotensin II) NO inhibitory of Flow contraction Pressure/stretch Sympathetic nerves (noradrenaline) Local hormones scular smooth muscle contraction noradrenaline, also a1 angiotensin II + & other vasoconstrictors rho kinase stretch + PIP2 Ca2+ sensitisation Na+, Ca2+ phospholipase C + PIP2 = phosphatidyl DAG + IP3 inositol 4,5 bisphosphate RGC + sarcoplasmic Na + reticulum + DAG = diacylglycerol SAC Ca2+ IP3 = inositol trisphosphate Na+ RGC = receptor-gated channel Membrane VGCC depolarisation + SAC = stretch activated channel Ca2+ gap junction VGCC = voltage-gated Ca2+ channel flow, bradykinin, Endothelial cell NO - mediated vasorelaxation acetylcholine, histamine, PGI2 etc NO SERCA + GC Ca2+ PMCA K+ K+ GTP channel + cGMP + GC = guanylate cyclase PDE SERCA = sarco/ endoplasmic reticulum Ca2+ ATPase Ca2+ desensitisation GMP PMCA = plasma VGCC membrane hyperpolarisation membrane Ca2+ ATPase PDE = phosphodiesterase Ca2+ cGMP activates protein kinase G yclic AMP - mediated vasorelaxation/opening of K+ channels Adrenaline, adenosine, b2 Ca2+ prostacyclin, etc 3Na+ H2O2 H2S SERCA Na+, Ca2+ exchanger EETs + AC + + K+ etc Ca2+ PMCA K+ K+ ATP AC = adenylate channel + cAMP + cyclase SERCA = sarco/endoplasmic PDE reticulum Ca2+ ATPase PMCA = plasma AMP VGCC membrane Ca2+ ATPase membrane hyperpolarisation EETs = epoxyeicosatrienoic acids cAMP activates protein kinase A Ca2+  Smooth muscle crossbridge cycling and its myosin heavy chains regulation actin binding ATP ATP Cross-bridge cycling is much myosin light chain kinase slower in smooth muscle + calmodulin compared to striated muscle. P P Ca2+ Ca2+ This leads to a much lower requirement for ATP. regulatory light chain Smooth muscle can MLC20 active complex remain contracted indefinitely F-Actin myosin P and doesn’t fatigue. myosin myosin actin inhibited by agonists via rho kinase: myosin ATP ‘Ca2+ sensitisation’ phosphatase Fast cross-bridge cycle This promotes generates force and contraction P activated by shortening NO via cGMP myosin ADP Blue = pro-contractile ‘Ca2+ desensitisation’ actin Red = pro-relaxant This promotes relaxation ulation of tension development in smooth muscle – latch brid Stimulus e.g. NA  Latch bridge formation would allow smooth muscle to maintain force myosin light chain kinase Ca2+ with less ATP expenditure. + calmodulin This may be another explanation Ca2+ Ca2+ tone for why smooth muscle requires