Differences in electromechanical coupling between bradykinin and the nonpeptide kinin B2 receptor agonist, FR 190997, in the circular muscle of guinea-pig colon.

We have compared the effect of bradykinin (BK) and the nonpeptide kinin B₂ receptor agonist, FR 190997, in producing changes in membrane potential and tension in the circular muscle of guinea-pig colon by the sucrose gap technique. In the presence of atropine (1 µM), S-ketoprofen (3 µM) and apamin (0.1 µM), BK (1 µM for 20 s) induced a transient depolarization of the membrane with superimposed action potentials (spikes) and transient contraction. Nifedipine (1 µM) eliminated the spikes and markedly inhibited the BK-induced contractions. FR 190997 (3–10 µM for 20 s) induced a slowly developing sustained small depolarization associated with a slowly developing and sustained contraction but, contrary to BK, FR 190997 was unable to trigger spikes. Nifedipine had no effect on depolarization and contraction induced by FR 190997. In the presence of 1 µM nifedipine, the combined application of a blocker of receptor-operated cation channels, SKF 96365 (50 µM for 30 min), and of an inhibitor of sarcoplasmic reticulum calcium pump, cyclopiazonic acid (CPA 10 µM for 30 min), reduced the BK-induced depolarization and contraction by about 45%–60%. The same treatment induced about 40% reduction of the sustained contraction induced by FR 190997, whereas the concomitant depolarization was not significantly affected. The tyrosine kinase inhibitor genistein (40 µM for 20 min) had no effect on the BK- and FR 190997-induced depolarization and contraction in the presence of nifedipine. In radioligand binding experiments performed in membranes of colonic smooth muscle cells, both agonists displaced the [³H]BK specific binding with a pIC₅₀ 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 B₂ receptors in guinea-pig colon. [ABSTRACT FROM AUTHOR]