Nonpeptide angiotensin II receptor antagonist recognizes inter-species differences in angiotensin AT 1 receptors

Abstract

Oral administration of the angiotensin AT 1 receptor antagonist 3-methyl-2,6-dimethyl-4-[[2′-(1 H-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 (pA 2=8.82) was about five times higher than that in the canine aorta (pA 2=8.18). The inhibition constant of ME3221 for displacing [ 125 I ]angiotensin II binding to membrane fractions from the rabbit aorta ( K i=3.84 nM) and rat liver ( K i=2.55 nM) was significantly lower than that for the canine aorta ( K i=84.5 nM), canine liver ( K i=122 nM) and bovine adrenal cortex ( K i=21.5 nM). In contrast, [Sar 1, Ala 8]angiotensin II had a similar inhibition constant ( K i=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 [ 125 I ]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 AT 1 receptor: the canine and bovine angiotensin AT 1 receptor has a relatively low affinity for ME3221 and is slightly resistant to dithiothreitol. The species difference in the angiotensin AT 1 receptor reflects the in vivo efficacy of ME3221 in rats and dogs.