Chan W Y, Wo N C, Manning M
Department of Pharmacology, Cornell University Medical College, NY 10021 USA.
Am J Obstet Gynecol. 1996 Nov;175(5):1331-5. doi: 10.1016/s0002-9378(96)70050-9.
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.
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.
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.
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.
本研究的目的是在大鼠模型中确定血管加压素的宫缩作用是由子宫中的血管加压素V1a受体介导、由催产素受体介导还是由两者共同介导。目的是评估催产素拮抗剂的抗V1a活性在早产的宫缩抑制治疗中是否是一种理想的药理学特性。
采用体外累积剂量反应曲线技术比较并分析催产素和精氨酸血管加压素宫缩作用的剂量反应特征。本研究选用了一种非选择性催产素-V1a受体拮抗剂、一种选择性催产素受体拮抗剂和一种选择性V1a受体拮抗剂。检测了它们在抑制离体大鼠子宫中由催产素和精氨酸血管加压素诱导的子宫收缩反应方面的相对效力。
催产素和精氨酸血管加压素的宫缩剂量反应曲线平行，且最大反应相同。非选择性催产素/V1a受体拮抗剂和选择性催产素受体拮抗剂在抑制由催产素或精氨酸血管加压素诱导的子宫收缩方面效力相同，而选择性V1a受体拮抗剂没有抗宫缩活性。选择性催产素拮抗剂的抑制作用使催产素和精氨酸血管加压素的剂量反应曲线类似地平行右移。
催产素和精氨酸血管加压素平行的剂量反应曲线表明血管加压素的宫缩作用也由催产素受体介导。精氨酸血管加压素与子宫中的催产素受体和V1a受体均结合，但V1a受体的激活似乎不是血管加压素子宫刺激作用的机制。催产素拮抗剂的抗V1a活性对宫缩抑制疗效无贡献，可能代表一种不良副作用。通过阻断血管V1a受体，它可能会损害患者在出血期间维持动脉血压的能力。
