In vivo pharmacology of SC-51316, a nonpeptidic angiotensin II receptor antagonist.
The depressor activity of a novel nonpeptidic angiotensin II (AII) receptor antagonist, SC-51316 (2,5-dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4 '- yl]-methyl]-3H-1,2,4-triazol-3-one), is described. In anesthetized, ganglion-blocked rats, intravenous administration of SC-51316 inhibited the pressor response to an infusion of AII. To determine antihypertensive efficacy, conscious, spontaneously hypertensive rats were administered SC-51316 (30 mg/kg intragastrically) daily for 5 days. Blood pressure was reduced in a similar manner to that observed with the angiotensin converting enzyme inhibitor enalapril (10 mg/kg intragastrically). SC-51316 had no effect on heart rate. In conscious, sodium-deficient dogs, administration of SC-51316 (30 mg/kg orally) or enalapril (10 mg/kg orally) lowered blood pressure similarly over a 24 h observation period. Thus, SC-51316 antagonizes the activity of AII in vivo and is an orally active, antihypertensive agent.
Olins
G M
GM
Department of Cardiovascular Diseases Research, G.D. Searle & Co., St. Louis, Missouri 63167.
Smits
G J
GJ
Koepke
J P
JP
Huang
H C
HC
Reitz
D B
DB
Manning
R E
RE
Blaine
E H
EH
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D003864:Depression, Chemical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D019808:Losartan; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D014230:Triazoles; D000804:Angiotensin II; C075064:SC 51316; D004656:Enalapril; D019808:Losartan