Pharmacological characterization of the nonpeptide angiotensin II receptor antagonist, U-97018.
We examined the pharmacological properties of U-97018, a novel nonpeptide angiotensin II (AII) receptor antagonist, in various in vitro and in vivo studies. U-97018 selectively displaced 125I-AII specific binding in the membrane fraction derived from the rat mesenteric artery and adrenal cortex (AT1 subtype) with IC50 of 1.3 +/- 0.2 and 7.7 +/- 1.3 nM, respectively, without altering the AII binding of the rat adrenal medulla (AT2 subtype). In rat adrenal cortical cells, U-97018 inhibited 1 nM AII-induced aldosterone secretion with an IC50 of 0.48 nM; it shifted concentration-secretion response curve for AII to the right and inhibited the maximal response to AII, yielding a pKB of 9.8. Similarly, U-97018 showed insurmountable antagonism with a pKB of 10.6 against the AII-induced contraction in the isolated rabbit aorta. U-97018 had no direct effect on the activities of renin and angiotensin converting enzyme in vitro. In pithed rats, U-97018 inhibited the AII-induced pressor response with an ED50 of 0.28 mg/kg, i.v. without any partial agonistic activity. In anesthetized rats and dogs, intraduodenal administration of U-97018 at a dose of 1 mg/kg inhibited the AII-induced pressor response by about 60%. In spontaneously hypertensive rats, U-97018 at 10 mg/kg p.o. produced antihypertensive effects which lasted for 24 hr after administration. Thus, U-97018 is an orally active, insurmountable AII receptor antagonist without any agonistic activity.
Kushida
H
H
Tsukuba Research Laboratories, Upjohn Pharmaceuticals Limited, Japan.
Nomura
S
S
Morita
O
O
Harasawa
Y
Y
Suzuki
M
M
Nakano
M
M
Ozawa
K
K
Kunihara
M
M
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism; D000313:Adrenal Medulla / Q000166:cytology / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis; D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004285:Dogs; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000378:metabolism; D012083:Renin / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D011724:Pyridazines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C095796:U 97018; D000804:Angiotensin II; D000450:Aldosterone; D000110:Acetylcholinesterase; D012083:Renin