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.