KT-362 related effects on intracellular calcium release and associated clinical potential: arrhythmias, myocardial ischemia, and hypertension

Abstract

The following discourse addresses the pharmacologic profile of KT-362, its clinical potential as an anti-arrhythmic agent with associated hypotensive effects, as well as its additional related potential in myocardial ischemia and related sequellae, and the specific cellular actions that may be responsible for these potential therapeutic effects. Although these include specific actions on both sodium and calcium entry, the focus is on the relevance of independent effects on calcium release. KT-362 relaxes arterial smooth muscle, concomitantly reducing the total peripheral resistance and mean arterial blood pressure. Vascular relaxing actions are attributed primarily to inhibitory effects on calcium release and secondarily to inhibitory effects on calcium entry via both potential-gated and receptor-linked channels. The "intracellular calcium antagonist" properties are correlated with a decrease in the production of the major second messenger, inositol 1,4,5-trisphosphate, which is responsible for calcium release and a concurrent ryanodine-like action that further decreases the amount of calcium released. Ventricular arrhythmias associated with coronary occlusion, cardiac glycosides, catecholamines, and chloroform are prevented by KT-362. General antiarrhythmic properties are associated with a use-dependent block of the "fast" sodium channel, primarily in the activated state, with ancillary effects on the "slow" calcium current. More selective effects on arrhythmias specifically associated with delayed after-depolarizations are attributed to effects on calcium release. In myocardial ischemia, KT-362 primarily reduces myocardial oxygen consumption rather than increases oxygen supply. The former is accomplished by depressing myocardial contractility and reducing afterload, while the latter is associated with a limited effect on coronary collateral blood flow. The negative inotropic effect is fundamentally related to its effects on calcium release, with additional contributions from its effects on calcium entry. Thus, the one intrinsic property of KT-362 that consistently emerges as significant and relevant in cardiovascular disease is the capacity to diminish calcium release.