Hemodynamic profile of a new antihypertensive agent D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine (SK&F 92657)

Abstract

The properties of a new antihypertensive agent, SK&F 92657, D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, have been studied. The compound, given intravenously, subcutaneously, or orally, caused a sustained fall in systemic blood pressure of conscious genetically hypertensive rats, normotensive cats, and renal hypertensive dogs. The fall in blood pressure of genetically hypertensive rats was maintained during 52 days of chronic dosing with no development of tolerance. The hemodynamic effects and mechanism of action of SK&F 92657 were investigated in anesthetized cats and dogs using a variety of techniques. Blood pressure was lowered by a direct vasodilator effect on precapillary blood vessels (arteries, arterioles), particularly in the renal, coronary, and skeletal muscle vasculatures, giving an overall decrease in total peripheral resistance with no significant change in cardiac output. In contrast, SK&F 92657 had no significant effect on capacitance blood vessel (veins, venules) tone or on vascular reactivity to vasoconstrictors and consequently did not cause postural hypotension. The beta-adrenoceptor-blocking actions of the drug prevented reflex increases in heart rate and cardiac output, except in the conscious dog, where vagal control of heart rate was predominant. It was also concluded that SK&F 92657 was not acting by alpha-adrenoceptor blockade, ganglion blockade, or inhibition of angiotensin II responses. A "central" action was unlikely, as SK&F 92657 caused vasodilatation in denervated autoperfused vascular beds.