Kinter L B, Caldwell N, Caltabiano S, Winslow C, Brooks D P, Huffman W F
Department of Pharmacology, Smith Kline & French Laboratories, Swedeland, Pennsylvania 19406-2799.
Am J Physiol. 1990 Mar;258(3 Pt 2):R763-9. doi: 10.1152/ajpregu.1990.258.3.R763.
Physiological regulation of receptor-effector pathways is recognized as a significant factor determining target organ selectivity and sensitivity in several hormonal systems. Whether or not physiological regulation of the renal vasopressin (V2) receptor-effector pathway participates in the control of body fluid homeostasis is unknown. We evaluated four states likely to be associated with altered sensitivities of the renal V2 receptor-effector pathway as follows: dehydration (18-h hydropenia), volume expansion, exogenous arginine vasopressin (AVP) infusion (10 ng/kg + 0.25 ng.kg-1.h-1), and cyclooxygenase blockade (indomethacin, 2 mg/kg + 2 mg.kg-1.h-1) for effects on the antidiuretic efficacies and potencies of putative V2-receptor antagonists in conscious dogs. The antidiuretic efficacies of desGly9[Pmp1-D-Tyr(Et)2Val4]AVP [Smith Kline & French (SK&F) 101926; 0.01-1,000 micrograms/kg] ranged from that of a full agonist to that of an antagonist, depending on the physiological state studied. The vasopressin antagonist potency of SK&F 101926 was increased 150-fold in association with extracellular volume expansion and decreased by blockade of renal cyclooxygenase activity. This spectrum of activities is that anticipated for a partial agonist under conditions where receptor number and/or sensitivity of receptor-effector coupling is increased or decreased, respectively. Thus volume expansion and increased circulating vasopressin concentration are associated with effective decreases, whereas hydropenia and cyclooxygenase blockade are associated with effective increases in sensitivity of the renal V2 receptor-effector pathway in the dog kidney. We conclude that the V2 receptor-effector pathway is a site of integration of physiological mechanisms participating in the control of body fluid homeostasis in conscious dogs.
受体 - 效应器途径的生理调节被认为是决定几种激素系统中靶器官选择性和敏感性的重要因素。肾血管加压素（V2）受体 - 效应器途径的生理调节是否参与体液平衡的控制尚不清楚。我们评估了四种可能与肾V2受体 - 效应器途径敏感性改变相关的状态，如下：脱水（18小时禁水）、容量扩张、外源性精氨酸血管加压素（AVP）输注（10 ng/kg + 0.25 ng·kg-1·h-1）以及环氧化酶阻断（吲哚美辛，2 mg/kg + 2 mg·kg-1·h-1），以研究其对清醒犬中假定的V2受体拮抗剂的抗利尿效力和效能的影响。去甘氨酸9[对甲基苯丙氨酸1 - D - 酪氨酸（乙基）2缬氨酸4]AVP[史克必成公司（SK&F）101926；0.01 - 1000微克/千克]的抗利尿效力根据所研究的生理状态不同，介于完全激动剂到拮抗剂之间。SK&F 101926的血管加压素拮抗剂效能在细胞外容量扩张时增加了150倍，而在肾环氧化酶活性被阻断时降低。这种活性谱是在受体数量和/或受体 - 效应器偶联敏感性分别增加或降低的情况下，部分激动剂所预期的。因此，容量扩张和循环血管加压素浓度增加与效力降低相关，而禁水和环氧化酶阻断与犬肾中肾V2受体 - 效应器途径敏感性有效增加相关。我们得出结论，V2受体 - 效应器途径是清醒犬中参与体液平衡控制的生理机制的整合位点。
