Differences in electromechanical coupling between bradykinin and the nonpeptide kinin B-2 receptor agonist, FR 190997, in the circular muscle of guinea-pig colon

We have compared the effect of bradykinin (BK) and the nonpeptide kinin B-2 receptor agonist, FR 190997, in producing changes in membrane potential an d tension in the circular muscle of guinea-pig colon by the sucrose gap tec hnique. In the presence of atropine (1 muM), S-ketoprofen (3 muM) and apamin (0.1 m uM), BK (1 CIM for 20 s) induced a transient depolarization of the membrane with superimposed action potentials (spikes) and transient contraction. Ni fedipine (1 CIM) eliminated the spikes and markedly inhibited the BK-induce d contractions. FR 190997 (3-10 muM for 20 s) induced a slowly developing s ustained small depolarization associated with a slowly developing and susta ined contraction but, contrary to BK, FR 190997 was unable to trigger spike s. Nifedipine had no effect on de polarization and contraction induced by F R 190997. In the presence of 1 CIM nifedipine, the combined application of a blocker of receptor-operated cation channels, SKF 96365 (50 muM for 30 min), and of an inhibitor of sarcoplasmic reticulum calcium pump, cyclopiazonic acid (C PA 10 muM for 30 min), reduced the BK-induced depolarization and contractio n by about 45%-60%. The same treatment induced about 40% reduction of the s ustained contraction induced by FR 190997, whereas the concomitant depolari zation was not significantly affected. The tyrosine kinase inhibitor genistein (40 muM for 20 min) had no effect o n the BK- and FR 190997-induced depolarization and contraction in the prese nce of nifedipine. In radioligand binding experiments performed in membranes of colonic smooth muscle cells, both agonists displaced the [H-3]BK specific binding with a pIC(50) of 9.6 and 8.5 for BK and FR 190997, respectively. These findings indicate a substantial qualitative difference in mechanisms of excitation contraction coupling activated by BK and FR 190997 via B-2 re ceptors in guineapig colon.