Pinacidil: history, basic pharmacology, and therapeutic implications.

Peripheral vasodilation has proved to be a successful method to control hypertension in recent years, as illustrated by the increasing number of marketed vasodilators like calcium antagonists, alpha-adrenergic antagonists, and angiotensin-converting enzyme inhibitors. A novel group of vasodilators showing excellent antihypertensive activity in spontaneously hypertensive rats and renal hypertensive dogs has been discovered. The first compounds of the group were pyridylthioureas. Chemical modification based on structure-activity studies involving a substitution of N-cyanoguanidine for the less active thiourea function has led to the synthesis of pinacidil, N'-cyano-N-(4-pyridyl)-N"-(1,2,2-trimethylpropyl) guanidine, recently introduced as the new antihypertensive drug, Pindac. Preclinical studies showed that pinacidil does not relax vascular smooth muscle by any known mechanism, but recent investigations indicate that the compound opens potassium channels in the cell membranes. The hyperpolarization that follows is responsible for the relaxation. Pinacidil is rapidly and almost completely absorbed after oral administration and produces a dose-dependent blood pressure fall in hypertensive animals and humans. The therapeutic plasma concentrations are in the range of those producing relaxation of isolated, noradrenalin-contracted human blood vessels in vitro. In dogs, pinacidil decreases vascular resistance in most tissues proportionally to the blood pressure fall, but elicits a specific increase in coronary blood flow at antihypertensive doses. The compound shows a selectivity for precapillary vessels. It is mainly eliminated by hepatic metabolism to pinacidil-N-oxide followed by renal excretion, and the N-oxidation is partly reversible. Pinacidil is relatively free of toxicity, and action-related side effects such as fluid retention and tachycardia are readily controlled with diuretics and beta-blockers.(ABSTRACT TRUNCATED AT 250 WORDS)