Analysis of the inhibitory effects of DuP 753 and EXP 3174 on responses to angiotensin II in the feline hindquarters vascular bed.
The effects of DuP 753 and EXP 3174, nonpeptide angiotensin II type 1 antagonists, on responses to angiotensin II were investigated in the hindquarters vascular bed of the cat. Under constant flow conditions, injections of angiotensin II into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Responses to the peptide were stable with respect to time, did not exhibit tachyphylaxis, and 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biph eny l-4-yl]methyl]methyl]imidazole (DuP 753) in doses of 1 and 2.5 mg/kg decreased vasoconstrictor responses to angiotensin II in a competitive manner, with a longer duration of action at the higher dose. DuP 753 had no significant effect on vasoconstrictor responses to vasopressin, norepinephrine, neuropeptide Y or 11 alpha,6 alpha-epoxymethano-9 alpha,11 alpha-dideoxy-prostaglandin F2 alpha, on biphasic responses to endothelin-1, or on vasodilator responses to acetylcholine. 2-n-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]im idazole-5-carboxylic acid (EXP 3174) also decreased responses to angiotensin II without altering responses to norepinephrine, vasopressin, U46619 or endothelin-1. The inhibitory effect of EXP 3174 was surmountable; however, large doses of angiotensin II were required, and the blockade was long in duration. The effects of DuP 753 and EXP 3174 on responses to angiotensin II and angiotensin III were similar, and when EXP 3174 was administered in doses of 0.1 and 0.05 mg/kg i.v., the blockade was overcome and the dose-response curves for angiotensin II were shifted to the right in a parallel manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Osei
S Y
SY
Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana.
Minkes
R K
RK
Bellan
J A
JA
Kadowitz
P J
PJ
D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000805:Angiotensin III / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D010477:Perfusion; D013777:Tetrazoles / Q000494:pharmacology*
D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D000805:Angiotensin III; C066026:losartan carboxylic acid; D019808:Losartan