Hormonal and cardiovascular effects of losartan (DuP753), an angiotensin receptor antagonist, in nonhuman primates.
Experiments were carried out in conscious dexamethasone-treated cynomolgus monkeys in an attempt to determine if losartan (DuP753) inhibited endogenous as well as exogenous angiotensin II stimulation of angiotensin receptors in vivo. Arterial blood pressure and heart rate were monitored via a radiotelemetry system and blood samples were obtained via vascular access ports for determination of plasma renin activity and plasma aldosterone (PA). Intravenous infusions of angiotensin II elicited reproducible pressor responses and increases in PA. The elevations of blood pressure and PA were completely blocked by losartan (10 mg/kg i.v.). Studies with normal monkeys showed that losartan (10 mg/kg i.v.) elicited a modest hypotension and hyper-reninemia without significantly altering PA. In contrast, studies with sodium-depleted monkeys showed that losartan (1 and 10 mg/kg i.v.) elicited hypotension, a decrease in PA and hyper-reninemia in a dose-related manner. Losartan did not significantly alter heart rate in either the normal or the sodium-depleted monkeys. These results were consistent with the conclusion that losartan was an inhibitor of endogenous as well as exogenous angiotensin II stimulation of vascular smooth muscle and adrenal cortical receptors.
DeGraaf
G L
GL
Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, Michigan.
Pals
D T
DT
Couch
S J
SJ
Lawson
J A
JA
D000450:Aldosterone / Q000097:blood / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005246:Feedback / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006728:Hormones / Q000097:blood*; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008252:Macaca fascicularis; D008297:Male; D012083:Renin / Q000097:blood; D012964:Sodium / Q000172:deficiency; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D006728:Hormones; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D000450:Aldosterone; D012964:Sodium; D012083:Renin; D019808:Losartan