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Smooth Muscle
Physiology and Pharmacology
| Question | Answer |
|---|---|
| Where is smooth muscle located | Widespread, often in the wall of hollow organs Gastro-intestinal tract Urinary tract Genital system Vascular/lymphatic systems Eyes Hair follicules |
| Clinical importance of smooth muscle | Smooth muscle dysfunction with age and disease can affect all major body systems E.g. CVS, angina, hypertension, asthma, hypo/hyper motility Incontinence, erectile dysfunction Many drugs target smooth muscle e.g. Hypertension- vascular smooth muscle |
| Common features of smooth muscle cells | Spindle shaped cells 4-8um diameter, 80-200 um length Much smaller than striated muscle No striations - myofilaments not arranged as sarcomeres No t-tubules Sarcoplasmic reticulum present but variable organisation |
| Old classification of smooth muscle | Cells are often arranged as functional bundles - multiunit and unitary Multiunit - electrical isolation allows finer motor control Unitary - gap junctions permit coordinated contraction All physically coupled by gap junctions |
| New classification of smooth muscle | Neurogenic Myogenic |
| Neurogenic | Quiescent cells that can be activated by nerves, hormones an autacoids e.g. smooth muscle of the iris and vascular smooth muscle of large arteries No spontaneous basal activity |
| Myogenic | Contracts spontaneously and modulated by nerves, hormones and autacoids E.g. smooth GI smooth muscle and vascular smooth muscle in small arteries Two subtypes - Electrically excitable (some GI smooth muscle) and less electrically excitable (vascular sm) |
| Action potentials in smooth muscle | Each action potential produces a contraction As the frequency of action potential increases contraction becomes tetanic APs carry Ca2+ into the cell which is involved in producing contraction |
| Gap junctions | Cells coupled via gap junctions - water filled pore between 2 cells formed by connexin proteins Allows coordinated function - muscle behaves as a syncytium Each cell membrane contains a hemichannel consisting of 6 connexins |
| Process of gap junction formation | Connexin synthesis Oligomerization ER-golgi passage Intracellular storage Trafficking along microtubules Plasma membrane insertion Lateral diffusion Gap junction assembly Stabilisation Annular gap junction Final degrading |
| How does Ca2+ trigger contraction | Agonists bind to receptors Activates IP3, which triggers Ca2+ influx from SR This triggers Ca2+ influx from extracellular via ligand and voltage gated channels 3 Ca bind to calmodulin, which activates myosin light chain kinase, activating myosin |
| Role of Ca2+ | Binds to calmodulin Smooth muscle lacks troponin Calmodulin, calponin thin filament proteins, inhibit myosin ATPase Inhibition removed by Ca-CaM complex Slow actin-myosin dissociation conserves energy |
| Increasing sensitivity to Ca2+ | Rho-kinase allows more force to be generated by the same Ca conc When activates, Rho kinase phosphorylates myosin phosphatase When activated, this enzyme removes the phosphate from myosin, inactivating it By inactivating the enzyme this is prevented |
| Smooth muscle relaxation | Ca is taken back up into the SR by SERCA proteins Excluded from the cell by the Ca-My ATPase and Na-Ca exchanger |
| Fluorescent reporter dyes | Visualise intracellular Ca2= Dye loaded into muscle Spontaneous Ca2+ sparks due to Ryr activation Ca2+ waves as a result of these sparks trigger contraction |
| Drugs for hypertension | Block or reverse vascular smooth muscle contraction Leads to arteriole vasodilation reducing vascular resistance to blood flow e.g L type voltage gated calcium channel blockers prevent Ca entry Adrenoreceptor antagonists block noradrenaline |
| Chemical classes of VGCC blockers | Dihydropyridines e.g. nifedipine and amlodipine Phenylalkylamines e.g. verapamil Benzothiazepines e.g. diltiazem |
| Binding sites of VGCC blockers | Diltiazem and verapamil bind deeply to the alpha subunit, channel must be open for them to bind (use-dependant) Nifedipine binds to a peripheral area of the alpha subunit so the channel does not have to be open (voltage dependant) |
| Experimental evidence that VGCC block causes relaxation | Application of VGCC block to isolated blood vessel causes an increase in diameter due to muscle relaxation Forced depolarisation of a blood vessel causes contraction as Ca enters. Application of a blocker relaxes the muscle |
| Drugs that stimulate relaxation | Viagra (Sildenafil) modifies intracellular second messenger signalling This is a type 5 phosphodiesterase inhibitor This increases smooth muscle cGMP which causes muscle relaxation by multiple routes particularly enhanced removal or cytoplasmic Ca |
| How increased cGMP causes relaxation | NO binds to soluble guanylyl cyclase which raises cGMP Sildenafil blocks PDE5 which would usually convert cGMP to GMP cGMP bind to ion channels, binds to proteins and activates PKG which decreases Ca conc |
| Role of cGMP dependant protein kinase type IB | Phosphorylates large conductance channels - hyperpolarisation blocks VGCC Inhibits IP3 generation Activates bound cGKIB to phosphorylate IP3 reducing Ca Enhances activity of myosin LC phosphatase - reduces sensitivity Phosphorylates ser-16 |
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