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

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 mumol/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. (C) 2004 Elsevier Inc. All rights reserved