Studies on the mechanism of the acute antihypertensive and vasodilator actions of several beta-adrenoceptor antagonists

Several new beta-adrenoceptor antagonists (sulfinalol, MK 761, and prizidilol) have been reported to possess direct vasodilator activity in addition to blocking beta-receptors. The mechanism of the hypotensive and vasodilator actions of these agents was examined and compared to that of pindolol and hydralazine. Intraarterial injection of each agent increased blood flow in the sympathetically denervated hindlimb of anesthetized dogs. Doses increasing flow by 50 ml/min (ED50) were 0.48, 0.24, 331, 0.3, and 51 micrograms for sulfinalol, MK 761, prizidilol, pindolol, and hydralazine, respectively, Intravenous injection of each agent reduced blood pressure of anesthetized, ganglion-blocked dogs. Vasodilation and hypotension to sulfinalol, MK 761, and pindolol, but not prizidilol or hydralazine were attenuated by propranolol pretreatment. Oral administration of sulfinalol (2.5 mg/kg), MK 761 (2.5 mg/kg), prizidilol (10 mg/kg), pindolol (0.1 mg/kg), and hydralazine (2.5 mg/kg) reduced pressure of conscious spontaneously hypertensive rats. Antihypertensive actions of sulfinalol and pindolol, but not MK 761, prizidilol, and hydralazine were inhibited by propranolol pretreatment (25 mg/kg, p.o.). With the exception of hydralazine, each agent demonstrated effective beta-adrenergic blockade at the antihypertensive dose tested as judged by inhibition of the chronotropic responses to sympathetic stimulation and isoproterenol in pithed rats. These data suggest that the acute vasodilator and blood pressure lowering effects of sulfinalol, MK 761, and pindolol, but not prizidilol and hydralazine, are mediated, at least in part, through activation of vascular beta-receptors.