The tachykinin NK1 receptor antagonist, RP67580, inhibits the bradykinin-induced rise in intracellular Ca2+ concentration in bovine pulmonary artery endothelial cells

The bradykinin-induced rise in intracellular Ca2+ concentration ([Ca2+](i)) and the bradykinin receptor involved in this response were characterized in bovine pulmonary artery endothelial cells. It was found that bradykinin induces an intracellular biphasic Ca2+ response, consisting of a transient peak followed by an elevated plateau phase. Both bradykinin and the bradykinin B-1 receptor agonist, des-Arg(9)-bradykinin, induced a concentration-dependent increase in [Ca2+](i), but the bradykinin-induced rise was much greater. Moreover, the bradykinin-induced [Ca2+](i) rise could be inhibited by the bradykinin B-2 receptor antagonists, D-Arg(0)[Hyp(3), Thi(5.8) D-Phe(7)]bradykinin and Hoe 140 (o-Arg[Hyp(3), Thi(5), D-Tic(7), Oic(8)]bradykinin), but not by the bradykinin B-1 receptor antagonist, des-Arg(9)-[Leu(8)]bradykinin. From these results it can be concluded that a bradykinin B-2 receptor is involved in this response. Furthermore, we found that the tachykinin NK1 receptor antagonist, RP67580 ([imino 1 (methoxy-2-phenyl)-2 ethyl]-2, diphenyl 7,7 perhydroisoindolone-4 (3aR, 7aR)), and its negative enantiomer, RP68651 (2-[1-imino 2-(2 methoxy phenyl) ethyl] 7,7 diphenyl 4-perhydroisoindolone (3aS-7aS)), could inhibit the bradykinin-induced [Ca2+](i) response, although no functional tachykinin NK1 receptors were found. Binding studies evidenced no binding of RP67580 or RP68651 to the bradykinin receptor. We conclude that RP67580 inhibits the bradykinin-induced rise in [Ca2+](i) via a bradykinin B-2 receptor-independent mechanism. (C) 1998 Elsevier Science B.V.