Effect of an oxytocin receptor antagonist and rho kinase inhibitor on the [Ca ++] i sensitivity of human myometrium

Abstract

Objective The purpose of this study was to assess the possible mechanism and effect of oxytocin receptor on the sensitization of the contractile proteins to [Ca ++] i. Study design Myometrial strips were prepared from biopsy specimens that had been taken at term (37–40 weeks of gestation) cesarean delivery from 22 women, before the onset of labor. Simultaneous measurements of [Ca ++] i and tension were performed on spontaneously contracting strips. The effects of a specific oxytocin receptor antagonist, L371,257, and a rho kinase inhibitor, Y-27632, on the [Ca ++] i and tension transients were determined. Results Application of L371,257 (90 nmol/L) to spontaneously contracting muscle strips reduced peak tension to 43%±12% of its original value without affecting peak [Ca ++] i (105%±15%). More tension is developed at each [Ca ++] i during the falling phase, relative to the rising phase of each spontaneous contraction; this asymmetric [Ca ++] i-tension relationship was abolished by L371,257. The subsequent application of oxytocin (3 μmol/L) reversed the effects of the antagonist on tension. An inhibitor of rho kinase (Y-27632) caused a concentration-dependent inhibition of spontaneous contractions without affecting the underlying Ca ++ signals. The addition of oxytocin (1 nmol/L) to spontaneously active myometrium increased both the duration of the Ca ++ signal and the sensitivity of the contractile machinery to [Ca ++] i; only the latter effect was prevented by Y-27632. Conclusion Oxytocin independently regulates the duration of the periodic Ca ++ signals and the sensitivity of the contractile machinery to Ca ++. The latter is likely to be mediated by rho kinase, which is essential for the effective coupling of increases in [Ca ++] i to tension.