Nonpeptide angiotensin II receptor antagonists: in vivo inhibition of [125I-Sar1,Ile8]angiotensin II binding by losartan, EXP597 and L-159,282 in rats.
Effects of losartan, L-159,282 and EXP597 on the in vivo binding of [125I-Sar1,Ile8]angiotensin II to kidney cortex and adrenal were examined in rats. Losartan, an AT1 receptor antagonist, completely blocked [125I-Sar1,Ile8]angiotensin II binding to the kidney cortex which contains only AT1 binding sites with an ID50 of 0.06 mg/kg. Losartan partially inhibited [125I-Sar1,Ile8]angiotensin II binding to the adrenal which contains equal amounts of AT1 and AT2 binding sites. Blockade by the AT1 receptor antagonist L-159,282 sufficiently increased the plasma levels of angiotensin II to block the AT2 receptor. EXP597 inhibited [125I-Sar1,Ile8]angiotensin II binding to the kidney cortex and adrenal almost totally with ID50s of 0.05 and 0.06 mg/kg, respectively. This result suggests that EXP597 exhibits almost equal binding affinity for AT1 and AT2 binding sites in vivo in rats.
Wong
P C
PC
Preclinical Pharmacology Group, DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400, USA.
Herblin
W F
WF
Barbera
F A
FA
Bernard
R
R
Bozarth
T A
TA
Watson
C A
CA
Gibson
R E
RE
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D013449:Sulfonamides; D013777:Tetrazoles; D000804:Angiotensin II; C090789:MK 996; C090811:EXP 597; C032651:angiotensin II, Sar(1)-Ile(5)-; D019808:Losartan