Effects of quinapril, a new angiotensin-converting enzyme inhibitor, on vasoconstrictor activity in the isolated, perfused mesenteric vasculature of hypertensive rats.
Previously, we had reported that 7-day administration of the angiotensin-converting enzyme inhibitor quinapril markedly reduced electrically evoked pressor responses in the isolated, perfused mesenteric vascular bed of the spontaneously hypertensive rat (SHR). In the present study, we investigated the possibility that quinapril alters postsynaptic vasoconstrictor activity to a variety of vasoconstrictive agents. Quinapril (10 mg/kg/day), administered orally to SHR for 7 days, significantly reduced the potency and the maximal vasopressor response to phenylephrine (2.5-fold and 40%, respectively) and the maximal response to serotonin (50%) compared with the responses from vehicle treated SHR. In contrast, quinapril had no significant effect on the pressor responses to KCl or phorbol ester. Furthermore, an equipotent antihypertensive dose of hydralazine (5 mg/kg/day, p.o., for 7 days) exerted no inhibitory effect on the pressor responses elicited by phenylephrine, KCl phorbol ester, but significantly reduced the maximal response to serotonin. In addition, vasopressor responses to phenylephrine were not affected by an acute (i.e., 75 min) infusion of quinaprilat, the active metabolite of quinapril. The results suggest that 7-day quinapril administration, and not acute treatment, reduces alpha 1 adrenoceptor and S2-serotonergic receptor-mediated vasoconstriction. However, quinapril did not reduce the vasoconstrictor responses induced by KCl or phorbol ester, indicating that those pressor responses that are due to depolarization or protein kinase C activation are, in part, independent of angiotensin-converting enzyme inhibition. This inhibition of vascular alpha 1 adrenoceptor and S2-serotonergic receptor pressor activity may underlie, in part, the long-term antihypertensive activity of quinapril in the SHR.
Major
T C
TC
Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan.
Overhiser
R W
RW
Taylor
D G
DG
Panek
R L
RL
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D006973:Hypertension / Q000503:physiopathology*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology*; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D000077583:Quinapril; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D044005:Tetrahydroisoquinolines; D014661:Vasoconstriction / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D012702:Serotonin Antagonists; D044005:Tetrahydroisoquinolines; D010656:Phenylephrine; D012701:Serotonin; D011189:Potassium Chloride; D013755:Tetradecanoylphorbol Acetate; D000077583:Quinapril