The role of oxytocin receptors and vasopressin V1a receptors in uterine contractions in rats: implications for tocolytic therapy with oxytocin antagonists.
OBJECTIVE
The objective of the study was to determine in the rat model whether the uterotonic action of vasopressin is mediated by the vasopressin V1a receptor in the uterus, by the oxytocin receptor, or by both. The purpose is to assess whether the anti-V1a activity of oxytocin antagonists is a desirable pharmacologic property in tocolytic therapy for preterm labor.


METHODS
Dose-response characteristics of the uterotonic action of oxytocin and arginine vasopressin were compared and analyzed by the in vitro cumulative dose-response curve technique. A nonselective oxytocin-V1a receptor antagonist, a selective oxytocin receptor antagonist, and a selective V1a receptor antagonist were selected for this study. Their relative effectiveness in inhibiting the uterine contractile responses induced by oxytocin and by arginine vasopressin in the isolated rat uterus was examined.


RESULTS
The uterotonic dose-response curves for oxytocin and arginine vasopressin were parallel and had the same maximal response. The nonselective oxytocin/V1a receptor antagonist and the selective oxytocin receptor antagonist were equally potent in inhibiting the uterine contractions induced by either oxytocin or arginine vasopressin, whereas the selective V1a receptor antagonist had no antiuterotonic activity. Inhibition by the selective oxytocin antagonist caused a similar parallel shift to the right of the dose-response curves for oxytocin and arginine vasopressin.


CONCLUSIONS
The parallel dose-response curves for oxytocin and arginine vasopressin suggest that the uterotonic action of vasopressin is also mediated by the oxytocin receptor. Arginine vasopressin binds to both oxytocin and V1a receptors in the uterus, but the activation of V1a receptors appears not to be a mechanism involved in the uterine-stimulating action of vasopressin. The anti-V1a activity of oxytocin antagonists does not contribute to tocolytic efficacy and may represent an undesirable side effect. By blocking the vascular V1a receptors, it may compromise the patient's ability to maintain arterial blood pressure during hemorrhage.
Chan
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WY
Department of Pharmacology, Cornell University Medical College, NY 10021 USA.
Wo
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Manning
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M
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D010121:Oxytocin / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D051381:Rats; D018045:Receptors, Oxytocin / Q000502:physiology*; D017483:Receptors, Vasopressin / Q000502:physiology*; D015145:Tocolysis; D014590:Uterine Contraction
D006727:Hormone Antagonists; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D010121:Oxytocin