Nonpeptide angiotensin II receptor antagonists. Studies with DuP 753 and EXP3174 in dogs.
DuP 753 (or EXP3174) and PD123177 are nonpeptide angiotensin (AII)-specific ligands, which show high affinities for two AII receptor subtypes, i.e. AT1 and AT2 sites, respectively. In furosemide-treated conscious dogs with high renin, DuP 753 and EXP3714, but not PD123177, were as effective as captopril in lowering blood pressure. Both DuP 753 and EXP3174 exhibited selective vascular antagonism of AII. In conscious dogs with normal renin, DuP 753, but not captopril or EXP3174, caused a dose-dependent but transient decrease in blood pressure. In anesthetized dogs, DuP 753 and captopril caused similar renal vasodilatation and natriuresis. The renal hemodynamic effects of DuP 753 and captopril were more pronounced in dogs with sodium depletion. These results suggest that the AT1 receptor mediates the pressor and renal effects of AII in dogs. The acute transient hypotensive effect of DuP 753 in normal-renin conscious dogs is probably unrelated to AII antagonism.
Wong
P C
PC
Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
Hart
S D
SD
Duncia
J V
JV
Timmermans
P B
PB
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005665:Furosemide / Q000008:administration & dosage; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects; D007677:Kidney Function Tests; D019808:Losartan; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D011863:Radioimmunoassay; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C066253:PD 123177; D005665:Furosemide; D002216:Captopril; C066026:losartan carboxylic acid; D019808:Losartan