Physiological regulation of the renal vasopressin receptor-effector pathway in dogs.
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.
Kinter
L B
LB
Department of Pharmacology, Smith Kline & French Laboratories, Swedeland, Pennsylvania 19406-2799.
Caldwell
N
N
Caltabiano
S
S
Winslow
C
C
Brooks
D P
DP
Huffman
W F
WF
D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000378:metabolism*; D009994:Osmolar Concentration; D011945:Receptors, Angiotensin / Q000502:physiology*; D017483:Receptors, Vasopressin; D014667:Vasopressins / Q000037:antagonists & inhibitors / Q000502:physiology*
D016861:Cyclooxygenase Inhibitors; D011945:Receptors, Angiotensin; D017483:Receptors, Vasopressin; D014667:Vasopressins; D001127:Arginine Vasopressin; C050890:1-((beta-mercapto-beta)beta cyclopentamethylenepropionic acid)-2-(O-ethyl-Tyr)-4-Val-9-des-Gly-arginine vasopressin