Modulation of Ca2+ Channel Activity, Protection of lschernic Myocardium, and Genesis of Arrhythrnias

The slow Ca2+ channels (L-type) of the heart are stimulated by cAMP. Elevation of CAMP produces a very rapid increase in number of slow channels available for voltage activation during excitation. The probability of a Ca2+ channel opening and the mean open time of the channel are increased. Therefore, any agent that increases the cAMP level of the myocardial cell will tend to potentiate ICa, Ca2+ influx, and contraction. The action of cAMP is mediated by PK-A and phosphorylation of the slow Ca2+ channel protein or an associated regulatory protein (stimulatory type) .The myocardial slow Ca2+ channels are also regulated by cGMP, in a manner that is opposite or antagonistic to that of cAMP. This has been demonstrated at both the macroscopic level (whole-cell voltage clamp) and the single channel level. The effect of cGMP is mediated by PK-G and phosphorylation of a protein, as for example, a regulatory protein (inhibitory-type) associated with the Ca2+ channel. It has been demonstrated that introduction of PK-G intracellularly causes a relatively rapid inhibition of ICa (L) in both chick and rat heart cells. In addition, cGMP/PK-G act to stimulate a phosphatase that dephosphorylates the Ca2+ channel.In addition to the slower indirect pathway……exerted via cAMP/PK-A……there is a faster more-direct pathway for ICa (L) stimulation by the β-adrenergic receptor. This latter pathway involves direct modulation of the channel activity by the alpha subunit (αs*) of the GS-protein. PK-C and calmodulin-PK also may play roles in regulation of the myocardial slow Ca2+ channels, possibly mediated by phosphorylation of some regulatory type of protein.Thus, it appears that the slow Ca2+ channel is a complex structure, including perhaps several associated regulatory proteins, which can be regulated by a number of factors intrinsic and extrinsic to the cell.The slow Ca2+ channels, which are selectively blocked by calcium antagonist drugs, are also selectively blocked rapidly and reversibly by acidosis. They require ATP for activity, as well. These special properties of the Ca2+ channels, not only allow regulation of the force of contraction of the heart, but also serve to protect the myocardial cells in ischemic regions from Ca2+ overload, ATP exhaustion, and cell death. The ATP-sensitive K+ channel (IK (ATp) ), whose activity is masked by normal [ATP], also serves to protect ischemic myocardium by shortening the cardiac action potential (AP), thereby terminating the Ca2+ influx prematurely and depressing contraction.Some types of arrhythmias are produced by delayed after-depolarizations (DADs) or oscillatory afterpotentials (OAPs), which are caused by spontaneous release of Ca2+ from SR that has been overloaded with Ca2+ The released Ca2+ acts to produce depolarization (the DAD), which then triggers a premature AP, via two mechanisms : (a) it turns on a Ca2+-activated nonselective cation (Na+, K+) channel, and (b) it stimulates the electrogenic Cai/Nao exchange reaction, which produces an inward depolarizing current. Both inward currents contribute to the arrhythmogenic transient inward current (Iti) . Thus, factors that stimulate Ca2+ influx or elevate [Ca] i, such as high drive rates, β-adrenergic agonists, or cardiac glycosides, predispose to this type of arrhythmia, known as triggered automaticity.