Pharmacology of LR-B/081, a new highly potent, selective and orally active, nonpeptide angiotensin Ⅱ AT_1 receptor antagonist

摘要

1. The pharmacological profile of LR-B/081, (methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1(6H)-pyrimidinyl]methyl]-3-thiophenecarboxylate), a novel antagonist at the angiotensin Ⅱ (AH) AT_1-receptor, was studied in vitro and in vivo. 2. In rabbit aortic strips incubated with LR-B/081 (1-1.000 nM), the concentration-response curve to AII was displaced to the right in a nonparallel fashion and the maximal contraction was progressively reduced, indicating that the compound is an insurmountable antagonist in this preparation (apparent pK_B = 9.50 ± 0.23). However, the interaction of LR-B/081 with AII receptors was found to be reversible, since the maximal response to AII was restored by coincubation with losartan, a surmountable AII AT_1-antagonist. Contractions elicited by KCl or phenylephrine were not affected by 10 μM LR-B/ 081. 3. In rat isolated perfused kidney, LR-B/081 and losartan antagonized the AII-induced vasoconstriction [IC_(50) (95% confidence limits) = 17(13-24) and 39(32-54) nM, respectively]. The LR-B/081 antagonism was incompletely reversed by excess AII, while losartan was fully displaced. The IC_(50) values of LR-B/081 and losartan obtained against vasoconstriction induced by endothelin-1 and noradrenaline were two orders of magnitude higher. 4. In pithed rats, the intravenous administration of LR-B/081 (0.2-2 μmol kg~(-1)) dose-dependently shifted to the right in a nonparallel fashion the dose-pressor response curve to AII. The maximal pressor response to AII was reduced by LR-B/081 in a dose-dependent fashion. The coadministration of losartan induced a progressive recovery of the maximal pressor response to AII, indicating that in vivo the interaction of LR-B/081 with AII receptors is reversible. LR-B/081 at 6 μmol kg~(-1), i.v. also did not affect the vasopressor response induced by noradrenaline in the pithed rat. 5. In conscious normotensive rats, single oral administration of LR-B/081 at 6 nmol kg~(-1) markedly inhibited the AII-induced pressor response; the inhibition lasted more than 24 h.