Nonpeptide angiotensin II receptor antagonist recognizes inter-species differences in angiotensin AT1 receptors.
Oral administration of the angiotensin AT1 receptor antagonist 3-methyl-2,6-dimethyl-4-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl ]methoxy] pyridine (ME3221) inhibited the pressor response to angiotensin II at doses of 0.3-1.0 mg/kg in rats. A higher dose of ME3221 (3-10 mg/kg) was required to obtain the same inhibitory potency in dogs. The antagonistic potency of ME3221 for angiotensin II-induced contraction in the rabbit aorta (pA2 = 8.82) was about five times higher than that in the canine aorta (pA2 = 8.18). The inhibition constant of ME3221 for displacing [125I]angiotensin II binding to membrane fractions from the rabbit aorta (Ki = 3.84 nM) and rat liver (Ki = 2.55 nM) was significantly lower than that for the canine aorta (Ki = 84.5 nM), canine liver (Ki = 122 nM) and bovine adrenal cortex (Ki = 21.5 nM). In contrast, [Sar1, Ala8]angiotensin II had a similar inhibition constant (Ki = 0.85-4.67 nM) in the species investigated. Treatment with 5 mM dithiothreitol significantly (P < 0.01) reduced the angiotensin II-induced contractile response to 1.2% in the rabbit aorta, but it did not significantly reduce the response in the canine aorta (83.2%). Dithiothreitol reduced [125I]angiotensin II binding to membrane fractions from the rabbit aorta and the rat liver but partially inhibited binding in preparations that had a low affinity for ME3221. These data indicate a species difference in the angiotensin AT1 receptor: the canine and bovine angiotensin AT1 receptor has a relatively low affinity for ME3221 and is slightly resistant to dithiothreitol. The species difference in the angiotensin AT1 receptor reflects the in vivo efficacy of ME3221 in rats and dogs.
Kawano
K
K
Drug Discovery Laboratories, Pharmaceutical Research Center, Meiji Seika Kaisha, Yokohama, Japan.
Fujishima
K
K
Nagura
J
J
Yasuda
S
S
Shinki
Hachisu
M
M
Konno
F
F
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D004285:Dogs; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011311:Pressoreceptors / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism; D012504:Saralasin / Q000494:pharmacology*; D013045:Species Specificity; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; C093897:ME 3221; D011945:Receptors, Angiotensin; D013439:Sulfhydryl Reagents; D013777:Tetrazoles; D012504:Saralasin; D004229:Dithiothreitol