Captopril inhibits the hydroosmotic effect of ADH in the cortical collecting tubule.
Previous studies have shown that captopril (CP) inhibits ADH-stimulated osmotic water permeability (Pf) in the toad bladder by potentiating endogenous bradykinin (BK). The present studies examine the effect of CP on ADH-stimulated Pf in isolated, perfused rabbit cortical collecting tubules (CCT). CP (10(-4) M) reversibly inhibited Pf, stimulated by maximal concentrations of ADH (10 microU/ml). Pretreatment of CCT's with 5 microM indomethacin, however, abolished the effect of CP. Inhibition of BK production by the kallikrein inhibitors, aprotinin and benzamidine, failed to enhance Pf stimulated by submaximal concentrations of ADH (2.5 microU/ml). Since ADH exerts its effects by activation of adenylyl cyclase (AC), further experiments were performed to identify the site at which CP inhibits this cascade. CP significantly inhibited forskolin (10(-4) M) stimulated Pf; however, it had no effect on cyclic AMP (10(-5) M) stimulated Pf, suggesting that the site of action is on the catalytic subunit or one of the GTP regulatory proteins of AC. To further localize the site of CP's action, CCT's were pre-incubated with pertussis toxin (0.5 microgram/ml) to inactivate the inhibitory, guanosine triphosphate (GTP) regulatory protein, Gi. In these tubules, CP failed to inhibit the action of ADH. We conclude that CP stimulates prostaglandin production which in turn activates Gi and inhibits AC activity. We further suggest that CP stimulates PG's directly, not via BK.
Rouse
D
D
Department of Medicine, Baylor College of Medicine, Houston, Texas.
Dalmeida
W
W
Williamson
F C
FC
Suki
W N
WN
D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors*; D002216:Captopril / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000502:physiology*; D007684:Kidney Tubules / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000502:physiology*; D011817:Rabbits; D014882:Water-Electrolyte Balance / Q000187:drug effects*
D001127:Arginine Vasopressin; D002216:Captopril