title: The tachykinin NK1 receptor antagonist, RP67580, inhibits the bradykinin-induced rise in intracellular Ca2+ concentration in bovine pulmonary artery endothelial cells.
abstract: 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 B1 receptor agonist, des-Arg9-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 B2 receptor antagonists, D-Arg0[Hyp3, Thi(5,8), D-Phe7]bradykinin and Hoe 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]bradykinin), but not by the bradykinin B1 receptor antagonist, des-Arg9-[Leu8]bradykinin. From these results it can be concluded that a bradykinin B2 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 B2 receptor-independent mechanism.
authors.affiliation: Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Westra-De Vlieger
authors.forename: P W
authors.initials: PW
authors.lastname: Van Den Wijngaard
authors.forename: A S
authors.initials: AS
authors.lastname: Koster
authors.forename: J
authors.initials: J
authors.lastname: Wilting
authors.forename: J
authors.initials: J
authors.lastname: Leysen
authors.forename: D
authors.initials: D
authors.lastname: Van Heuven-Nolsen
authors.forename: F P
authors.initials: FP
authors.lastname: Nijkamp
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005456:Fluorescent Dyes; D016257:Fura-2; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*
chemical_list: D005456:Fluorescent Dyes; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D001920:Bradykinin; D002118:Calcium; D016257:Fura-2