AJP - Regulatory, Integrative and Comparative Physiology, Vol 258, Issue 3 763-R769, Copyright © 1990 by American Physiological Society
Physiological regulation of the renal vasopressin receptor-effector pathway in dogs
L. B. Kinter, N. Caldwell, S. Caltabiano, C. Winslow, D. P. Brooks and W. F. Huffman
Department of Pharmacology, Smith Kline & French Laboratories, Swedeland, Pennsylvania 19406-2799.
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.
