NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONIST RECOGNIZES INTERSPECIESDIFFERENCES IN ANGIOTENSIN AT(1) RECEPTORS

Oral administration of the angiotensin AT, receptor antagonist [2'-(1H -tetrazol-5-yl)-1,1'-biphenyl-4-yl]methoxy] pyridine (ME3221) inhibite d the presser 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 fo r 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 [I-125]angioten sin 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 f or the canine aorta (K-i = 84.5 nM), canine liver (K-i = 122 nM) and b ovine adrenal cortex (K-i = 21.5 nM). In contrast, [Sar(1), Ala(8)]ang iotensin II had a similar inhibition constant (K-i = 0.85-4.67 nM) in the species investigated. Treatment with 5 mM dithiothreitol significa ntly (P < 0.01) reduced the angiotensin II-induced contractile respons e to 1.2% in the rabbit aorta, but it did not significantly reduce the response in the canine aorta (83.2%). Dithiothreitol reduced [I-125]a ngiotensin 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 i n 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 do gs. (C) 1998 Elsevier Science B.V. All rights reserved.