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).


METHODS
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 micromol/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.


CONCLUSIONS
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.
Woodcock
Nicola A
NA
Department of Biological Sciences, University of Warwick, Walsgrave Hospital, Coventry, United Kingdom, UK. Nicola.Woodcock@warwick.ac.uk
Taylor
Colin W
CW
Thornton
Steven
S
D000328:Adult; D000577:Amides / Q000494:pharmacology; D048588:Benzoxazines; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D009215:Myometrium / Q000378:metabolism*; D009994:Osmolar Concentration; D010078:Oxazines / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors / Q000502:physiology*; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases
D000577:Amides; D048588:Benzoxazines; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C096766:L 371257; D010078:Oxazines; D010880:Piperidines; D011725:Pyridines; D018045:Receptors, Oxytocin; C108830:Y 27632; D010121:Oxytocin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D002118:Calcium