Li X, Kribben A, Wieder E D, Tsai P, Nemenoff R A, Schrier R W
Department of Medicine, University of Colorado School of Medicine, Denver.
Hypertension. 1994 Feb;23(2):217-22. doi: 10.1161/01.hyp.23.2.217.
In vascular smooth muscle cells arginine vasopressin acting through the V1 receptor increases intracellular Ca2+, leading to vasoconstriction. Recent studies have also shown that vasopressin activates mitogen-activated protein kinase (MAP kinase), which may contribute to vasopressin-induced hypertrophy of vascular smooth muscle cells. We examined the ability of an orally active, nonpeptide selective V1 antagonist (OPC-21268) to block vasopressin binding and postreceptor signaling in these cells. [3H]Vasopressin binding at 2 x 10(-9) mol/L was half-maximally blocked at 10(-9) mol/L OPC-21268. To compare effects of OPC-21268 on binding and postreceptor signaling, we stimulated cells with 10(-8) mol/L vasopressin. At this vasopressin concentration, half-maximal inhibition of binding occurred at 5 x 10(-9) mol/L OPC-21268. Half-maximal inhibition of Ca2+ efflux or increases in intracellular free Ca2+ required higher concentrations of antagonist (10(-7) mol/L), and half-maximal inhibition of vasopressin-stimulated MAP kinase was observed only at 10(-6) mol/L OPC-21268. These results indicate that this agent selectively blocks both vasopressin binding and postreceptor signaling in vascular smooth muscle cells. The requirement of higher concentrations of OPC-21268 for blocking increases in intracellular Ca2+ and activation of MAP kinase suggests that binding to a fraction of V1 receptors generates maximal levels of second messengers or the existence of subtypes of the V1 receptor with differential affinity for this antagonist. These data have implications for the clinical use of this compound.
在血管平滑肌细胞中，精氨酸加压素通过V1受体发挥作用，增加细胞内钙离子浓度，导致血管收缩。最近的研究还表明，加压素可激活丝裂原活化蛋白激酶（MAP激酶），这可能与加压素诱导的血管平滑肌细胞肥大有关。我们研究了一种口服活性非肽类选择性V1拮抗剂（OPC-21268）阻断这些细胞中加压素结合及受体后信号传导的能力。在2×10⁻⁹ mol/L时，[³H]加压素结合被10⁻⁹ mol/L OPC-21268半数最大阻断。为比较OPC-21268对结合及受体后信号传导的影响，我们用10⁻⁸ mol/L加压素刺激细胞。在此加压素浓度下，5×10⁻⁹ mol/L OPC-21268时出现结合的半数最大抑制。钙离子外流或细胞内游离钙离子增加的半数最大抑制需要更高浓度的拮抗剂（10⁻⁷ mol/L），仅在10⁻⁶ mol/L OPC-21268时观察到加压素刺激的MAP激酶的半数最大抑制。这些结果表明该药物可选择性阻断血管平滑肌细胞中加压素的结合及受体后信号传导。阻断细胞内钙离子增加及MAP激酶激活需要更高浓度的OPC-21268，这表明与一部分V1受体结合可产生最大水平的第二信使，或存在对该拮抗剂亲和力不同的V1受体亚型。这些数据对该化合物的临床应用具有重要意义。
