Mechanism of diuretic action of U-62,066E, a kappa opioid receptor agonist.
The mechanism of the diuretic action of U-62,066E, a highly selective kappa opioid agonist, was examined in unanesthetized rats and in isolated perfused inner medullary collecting ducts (IMCD). In Long-Evans rats, U-62,066E caused a dose-dependent increase in urine flow and a decrease in urine osmolality without affecting urinary excretion of Na+. The diuretic effect of U-62,066E was blocked by MR-2266, a kappa opioid receptor antagonist. U-62,066E showed no diuretic effect in homozygous hereditary diabetes insipidus rats (Brattleboro strain). In water-deprived rats, U-62,066E markedly inhibited plasma arginine vasopressin (AVP) levels through a kappa receptor-mediated mechanism. In rat IMCD perfused in vitro, 10(-5) M U-62,066E did not inhibit either the baseline or the AVP-stimulated osmotic water permeability. We conclude that the inhibition of the release of AVP is the major if not the entire mechanism of the diuretic action of U-62,066E in rats. Although we ruled out the effect of this drug on the water permeability of IMCD, possible direct effects on other nephron structures remain to be established.
Yamada
K
K
2nd Department of Internal Medicine, School of Medicine, Chiba University, Japan.
Imai
M
M
Yoshida
S
S
D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors* / Q000097:blood; D001575:Benzomorphans / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007685:Kidney Tubules, Collecting / Q000187:drug effects; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects; D009994:Osmolar Concentration; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011913:Rats, Inbred BB; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects; D017473:Receptors, Opioid, kappa
D001575:Benzomorphans; D004232:Diuretics; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D001127:Arginine Vasopressin; C027247:MR 2266; C051272:spiradoline