Nonpeptide angiotensin II receptor antagonists. I. Pharmacological characterization of 2-n-butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5-acetic acid, sodium salt (S-8307).
2-n-Butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5-acetic acid, sodium salt (S-8307) displaced [3H]angiotensin II (All) from its specific binding sites in rat adrenal cortical membranes with an IC50 of 4 x 10(-5) M. In rabbit aorta, S-8307 competitively inhibited the contractile response to All with a pA2 value of 5.49 but at 10(-4) M it did not alter the response to norepinephrine or KCI. Similarly, a specific AII antagonism was shown in vivo in the spinal pithed rat model. In anesthetized rats, S-8307 did not potentiate the bradykinin vasodepressor response. In renal artery-ligated rats, a high renin model, S-8307 decreased mean blood pressure at 10 and 30 mg/kg i.v. as well as at 100 mg/kg p.o. In anesthetized rats, furosemide enhanced the hypotensive effect of S-8307. Blockade of the renin-angiotensin system by captopril, saralasin or bilateral nephrectomy inhibited significantly but did not abolish completely the hypotensive effect of S-8307 in furosemide-treated rats. Inhibition of prostaglandin synthesis by indomethacin did not significantly reduce the hypotensive effect of S-8307. Our results identify S-8307 as a selective antagonist of AII receptors. However, at higher doses, mechanisms other than AII receptor blockade may partly account for its acute hypotensive effect.
Wong
P C
PC
Medical Products Department, E.I. du Pont de Nemours & Company, Inc., Wilmington, Delaware.
Chiu
A T
AT
Price
W A
WA
Thoolen
M J
MJ
Carini
D J
DJ
Johnson
A L
AL
Taber
R I
RI
Timmermans
P B
PB
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005665:Furosemide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011453:Prostaglandins / Q000502:physiology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011453:Prostaglandins; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C057359:2-n-butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5-acetic acid; D005665:Furosemide; D001920:Bradykinin