Yamada Y, Yamamura Y, Chihara T, Onogawa T, Nakamura S, Yamashita T, Mori T, Tominaga M, Yabuuchi Y
Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co, Ltd, Tokushima, Japan.
Hypertension. 1994 Feb;23(2):200-4. doi: 10.1161/01.hyp.23.2.200.
We studied the hypotensive effects of OPC-21268, an orally effective nonpeptide vasopressin V1 receptor antagonist, in spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP). OPC-21268 was given intravenously to conscious, freely moving SHR and SHRSP. We used young and aged animals to examine the contribution of vasopressin to the development and maintenance of hypertension in both types of rats. In SHR, hypertension was fully established at 38 weeks of age, and intravenous injection of OPC-21268 produced slight hypotensive effects at either 38 or 70 weeks of age. In SHRSP, hypertension developed at 25 weeks of age, and blood pressure was sustained at a high level (approximately 250 mm Hg systolic blood pressure) thereafter. Intravenous administration of OPC-21268 did not cause hypotensive effects in young rats at 15 weeks, but at 25 weeks a significant decrease in blood pressure was observed. Furthermore, in the malignant state of SHRSP (35 to 41 weeks), OPC-21268 significantly decreased mean blood pressure by 32.4 +/- 7.9 mm Hg (mean +/- SEM) at 3 mg/kg IV, and the decrease was dose dependent (0.3 to 3.0 mg/kg). Plasma vasopressin concentrations were increased in a more malignant phase of SHRSP at 45 weeks of age, whereas at other ages of SHRSP or in SHR, plasma vasopressin levels were not increased. These results suggest that vasopressin plays an important role through V1 receptors in the maintenance of hypertension, at least in the malignant phase of SHRSP, and OPC-21268 may be therapeutically useful in the treatment of some types of hypertension.
我们研究了口服有效的非肽类血管加压素V1受体拮抗剂OPC - 21268对自发性高血压大鼠（SHR）和易卒中型SHR（SHRSP）的降压作用。将OPC - 21268静脉注射给清醒、自由活动的SHR和SHRSP。我们使用年轻和老年动物来研究血管加压素在这两种大鼠高血压发生和维持中的作用。在SHR中，高血压在38周龄时完全形成，静脉注射OPC - 21268在38周龄或70周龄时产生轻微的降压作用。在SHRSP中，高血压在25周龄时出现，此后血压维持在高水平（收缩压约250 mmHg）。静脉注射OPC - 21268在15周龄的年轻大鼠中未引起降压作用，但在25周龄时观察到血压显著下降。此外，在SHRSP的恶性阶段（35至41周），静脉注射3 mg/kg的OPC - 21268可使平均血压显著降低32.4 +/- 7.9 mmHg（平均值 +/- 标准误），且降压作用呈剂量依赖性（0.3至3.0 mg/kg）。在45周龄的SHRSP更恶性阶段，血浆血管加压素浓度升高，而在SHRSP的其他年龄阶段或SHR中，血浆血管加压素水平未升高。这些结果表明，血管加压素至少在SHRSP的恶性阶段通过V受体在高血压维持中起重要作用，并且OPC - 21268在某些类型高血压的治疗中可能具有治疗作用。
