BRADYKININ-INDUCED BIPHASIC RESPONSE IN THE RAT ISOLATED STOMACH FUNDUS - FUNCTIONAL EVIDENCE FOR A NOVEL BRADYKININ RECEPTOR

The responses of the rat isolated stomach fundus to bradykinin (BK) and des-Arg9-BK (DA-BK) have been examined. In rat isolated stomach fundus pre-contracted with BaCl2 (0.5-1 mM), BK caused concentration-dependent biphasic responses characterized by relaxation followed by contraction. DA-BK also caused marked relaxations, but, unlike BK, induced only small contractions. Removal of the mucosal layer initially abolished the relaxant responses to BK and both responses to DA-BK without affecting BK-induced contractions, but repeated challenges with BK or DA-BK revealed a time-dependent reappearance of the relaxant responses, suggesting "de novo" synthesis of BK receptors. Pretreatment of rat stomach fundus with tetrodotoxin (1-mu-M), atropine (1-mu-M), captopril (3-mu-M), prazosin (1-mu-M) or glibenclamide (1-mu-M) did not significantly modify the biphasic responses to BK (300 mM). The biphasic responses to DA-BK were antagonized selectively by the B1 receptor antagonist des-Arg9-[Leu8]-BK (DAL-BK) (1-mu-M). In contrast, the biphasic responses to BK were unaffected by DAL- BK or by several selective peptide antagonists of B2 receptors including NPC 431 (Thi5,8,D-Phe7)-BK, NPC, 349 (D-Arg Hyp3,Thi5,8,D-Phe7)-BK, NPC 567 (D-Arg -Hyp3,D-Phe7)-BK and NPC 361 (D-Phe7)-BK (3 to 10-mu-M). These results are consistent with the view that the biphasic responses of the rat isolated stomach fundus to BK appear to be mediated by a novel BK receptor which is insensitive to blockade by B1 and B2 selective BK receptor antagonists.