Abstract

Ro 12-4713, an oxadiazolopyrimidine derivative, lowered blood pressure of conscious spontaneously hypertensive rats and renal hypertensive dogs in a dose-dependent manner from 10 to 100 mg/kg p.o. The antihypertensive effect was slow in onset, had a long duration of action and was not subject to the development of tachyphylaxis. Ro 12-4713 did not influence blood pressure in conscious normotensive rats, cats and dogs. Several observations suggest that metabolites formed from the inactive parent compound are responsible for the cardiovascular effects. A hemodynamic analysis in anesthetized dogs showed that Ro 12-4713 lowered blood pressure and peripheral vascular resistance. These effects were associated with an increase in cardiac output and flow in various vascular beds as well as with an increase in myocardial contractility. This pattern of hemodynamic activity together with the absence of effects on the autonomic neuroeffector system allow the classification of Ro 12-4713 as a vasoactive antihypertensive agent like e.g. hydralazine or minoxidil. However, in contrast to other vasoactive antihypertensives, Ro 12-4713 virtually did not produce tachycardia or water and sodium retention. Ro 12-4713 may represent a considerable improvement in current vasodilator antihypertensive therapy.