Non-peptide angiotensin II receptor antagonists. II. Pharmacology of S-8308.
2-Butyl-4-chloro-1-(2-nitrobenzyl)imidazole-5-acetic acid, sodium salt (S-8308), inhibited the specific binding of labeled angiotensin II (AII) to its receptor sites in rat adrenal cortical microsomes and in cultured aortic smooth muscle cells with IC50S of 15 and 4.5 microM, respectively. In the presence of S-8308 (15 microM) the dissociation constant for AII was increased 2-fold and the total number of binding sites was unaltered. In a concentration-dependent manner S-8308 blocked the 45Ca2+ influx induced by AII (3 X 10(-8) M) in rat aortic rings (IC50 7 microM) and the contractile response in rabbit aorta was competitively inhibited (pA2 = 5.74). This agent was highly specific for AII: it showed no affinity for alpha 1-adrenoceptors or Ca2+ channels and in addition, it did not alter the contractile responses to norepinephrine (10(-7) M) or KCl (55 mM). In conscious renal artery-ligated rats, S-8308 (30 mg/kg i.v.) elicited a rapid decrease of mean arterial pressure with a duration of about 30 min. The results demonstrate that S-8308 is a weak, but specific and competitive, non-peptide antagonist of AII exerting its inhibitory action at the receptor level.
Chiu
A T
AT
Medical Products Department, E.I. du Pont de Nemours & Company, Inc., Wilmington, DE 19898.
Carini
D J
DJ
Johnson
A L
AL
McCall
D E
DE
Price
W A
WA
Thoolen
M J
MJ
Wong
P C
PC
Taber
R I
RI
Timmermans
P B
PB
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D005260:Female; D006977:Hypertension, Renal / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000187:drug effects* / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D007093:Imidazoles; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C058909:S 8308; D002118:Calcium