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Smooth Muscle Physiology (Smooth muscle (Involuntary and lines hollow…

- - - - 2 Essential myosin light chains
      - 2 Myosin heavy chains
        
        Site of actin binding, ATP hydrolysis, and force generation
        
        4 Isoforms (2 mutations at each end)
        
        Tonic smooth muscle encodes for a slower, more energy efficient contraction (aorta)
        
        Phasic smooth muscle faster contracting muscle (bladder) [is still much slower than slow skeletal muscle]
        
        Both tonic and phasic contraction produce the same force as skeletal muscle but are orders of magnitude slower than skeletal and cardiac muscle
        
        Faster muscle produces higher power, but consumes more energy
      - 2 Regulatory Myosin light chains
        
        Controls activation
        
        Activation controlled by phosphorylation
        
        Calcium binds to calmodulin (4 calciums) which activates myosin light chain kinase which phosphorylates R-MyLC. Once phosphorylated, the MyHC goes through conformational change and allows actin-myosin interaction
        
        MyLC phosphatase removes the phosphate, ending the contraction
        
        Increased activity of MLCK sends reaction to activated contraction from R-MyLC
        
        Relative activation of MLCK and MLCP determine the amount of force being generated by the muscle
        
        Neuromuscular transmitters all seem to act by affecting either calcium, MLCK, or MLCP
      - Acto-myosin crossbridge cycle
        
        Chemical energy in ATP converted to mechanical energy by the myosin protein
- - - - Regulation determines contracting or relaxing
        
        Myosin light chain kinase phosphorylates (stim contraction)
        
        Calcium controls activity of MLCK (but not MLCP)
        
        Myosin light chain phosphatase dephosphorylates (stim relaxation)
- - - - causes recurrent cough, wheezing, and dyspnea
      - Tx: glucocorticoids and bronchodilators
    - - urinary calculi/mucus forms a mechanical obstruction of the urethra
        
        urine backs up into bladder and then kidneys
        
        Tx: mechanically opening the urethra, emptying bladder
        
        If long term obstruction: Atonic bladder due to distension of bladder wall. Damage is due to the lack of stretch existing in the nerves, not damage to the smooth muscle
        
        Tx: Bethanechol - muscarinic agonist with selective activity in the detrusor muscle
        
        Using drugs specific to the organ of interest is critical with medications affecting smooth muscle
- - - - Nicotinic - skeletal muscle, CNS, no second messenger
      - Muscarinic: smooth muscle, CNS, G-protein linked
- - - - decreased calcium calmodulin complex, causing decreased MLCK activity, causing decreased myosin activation and force
        
        Tx: SLOW calcium administration
        
        Similar effects seen in milk fever cows in rumen and abomasum
  - - - increased renal renin secretion leads to activation of angiotensin II (vasoconstriction) and aldosterone (sodium resorption)
        
        Tx: amlodipine (Calcium channel blocker). Decrease calcium influx decreases force in vascular smooth muscle, lowering blood pressure
        
        Tissue specificity is important, as it has minimal cardiac effects
  - - - Rapid drops in blood pressure are required immediately
        
        Tx: nitropusside
        
        Nitric Oxide (NO) aka Endothelial Derived Relaxing Factor
        
        Produced by endothelial lining of blood vessels due to shear forces or inflammatory mediators
        
        cNOS (enzyme) produces it
        
        Pharmacologically this mediates the effects of nitroglycerin and Viagra. causes vasodilation via 2nd messenger that lowers intracellular calcium
  - - - Calcium sensitization-- MLCP activity inhibited, resulting in increase in phosphorylated R-MLC, despite no increase in calcium
        
        note how Rho-kinase inhibition and stimulation will affect smooth muscle activation
        
        overexpression of Rho-kinase results in increased spontaneous contractions