MECHANISM OF THE ANTIHYPERTENSIVE EFFECT OF DIAZOXIDE: IN VITRO VASCULAR STUDIES IN THE HYPERTENSIVE RAT

¹ Department of Pharmacology, Schering Corporation, Bloomfield, New Jersey

Several authors have shown that diazoxide is a more potent hypotensive agent in intact rats with various forms of hypertension than in normal rats. The present study extends and confirms those results, but at the vascular level in terms of the competition of diazoxide with the aortic vasoconstrictor action of barium ion. The pA₂ for the diazoxide-barium interaction in normal rats is 4.72 ± 0.06 (S.E.M.), and in age-matched desoxycorticosterone-hypertensive rats the pA₂ is 5.05 ± 0.07. This difference is statistically significant. Similar studies of the competitive interaction between phentolamine and norepinephrine showed no significant differences when similar test groups were compared. The doubled potency of diazoxide in the hypertensive animals in vitro amounts to a quantitative correlation with the drug's increased antihypertensive potency in vivo, and is interpreted as implicating the competitive blockade in the antihypertensive mechanism. Studies designed to analyze this increased potency indicate that a partial answer may lie in the inability of normal tissue to retain diazoxide-blocking activity. The basis for this latter finding may be the reported differences in calcium metabolism by normal and hypertensive blood vessels.