1. Cardiac excitation-contraction coupling and its regulation by positive inotropic drugs. The cardiac cycle is initiated by membrane depolarization, which causes the opening of voltage-dependent Na+ and L-type Ca2+ channels, permitting Na+ and Ca2+ flow down their electrochemical gradients into the myocyte. Thus, Na+ and Ca2+ enter the cardiac myocyte during each cycle of membrane depolarization, triggering the release, through the RyR, of larger amounts of Ca2+ from internal stores in the SR. The resulting increase in intracellular Ca2+ interacts with troponin C and activates interactions between actin and myosin that result in sarcomere shortening. The electrochemical gradient for Na+ across the sarcolemma is maintained by active transport of Na+ out of the cell by the sarcolemmal Na+/K+ ATPase (NKA). The bulk of cytosolic Ca2+ (70%) is pumped back into the SR by a Ca2+-ATPase, SERCA2. The remainder is removed from the cell by either a sarcolemmal Ca2+-ATPase or a high-capacity NCX. The NCX exchanges three Na+ for a Ca2+, using the electrochemical potential of Na+ to drive Ca2+ extrusion. The β adrenergic agonists (acting at βAR, the β adrenergic receptor) and PDE inhibitors, by increasing intracellular cAMP levels, activate PKA, which phosphorylates PLB in the SR, the α subunit of the L-type Ca2+ channel, and regulatory components of the RyR, as well as TnI. As a result, the probabilities of opening of the L-type Ca2+ channel and the RyR2 Ca2+ channel are increased; SERCA2 inhibition by PLB is released, with the result that SERCA2 accumulates Ca2+ into the SR faster, more avidly, and to a higher concentration; and relaxation occurs at slightly higher [Ca2+]i due to slightly reduced sensitivity of the troponin complex to Ca2+. The net effect of these phosphorylations is a positive inotropic effect: a faster rate of tension development to a higher level of tension, followed by a faster rate of relaxation. CGs, by inhibiting the Na+/K+ ATPase, reduce Na+ extrusion from the cell, thereby permitting [Na+]in to rise, reducing the inward gradient for Na+ that drives Ca2+ extrusion by NCX. As a consequence, Ca2+ accumulates in the SR, and a positive inotropic effect follows, as noted previously for the effect of increased cellular cAMP. See the text for details of additional effects of CGs. Note that, under steady-state conditions, the amount of Ca2+ leaving the cell exactly matches the amount entering it. As NCX exchanges three Na+ for every Ca2+, it creates a depolarizing current. This makes not only the direction of transport dependent on the chemical gradients of Na+ and Ca2+ across the membrane but also the membrane potential. Thus, the direction of Na+-Ca2+ exchange may briefly reverse during depolarization, when the electrical gradient across the sarcolemma is transiently reversed. PLM is an tonic inhibitor of the Na+/K+ ATPase, which supplies the driving force (an appropriately low [Na+]in) for maintaining low diastolic Ca2+. Phosphorylation of PLM by PKA removes this inhibitory influence, thereby stimulating the activity of the Na+/K+ ATPase and limiting [Na+]in and [Ca2+]in. This may reduce the tendency toward arrhythmias during adrenergic stimulation (see Pavlovic et al., 2013).
Source: Therapy of Heart Failure, Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e
Citation: Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2017 Available at: Accessed: October 21, 2017
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