Studies on the nature and mechanism of the diuretic activity of the opioid analgesic ethylketocyclazocine

Abstract

Subcutaneous injection (0.1 - 3.0 mg/kg) of ethylketocyclazocine (EKC; a prototype kappa agonist) resulted in a dose-dependent increase in urine formation in conscious rats. The increase in urine volume was unaccompanied by a corresponding increase in electrolyte excretion; thus, EKC behaved like a "water diuretic." The diuretic activity was completely abolished by naltrexone, an opiate antagonist. Water loading (10 ml/kg) and EKC (0.5 mg/kg) diminished plasma vasopressin levels equally 60 min after treatment. However, urine formation during the 1 st hr was greater in EKC-treated rats than in water-loaded rats. These results suggested that more than one component was responsible for the diuretic activity of EKC. A central effect of EKC on plasma vasopressin and urine volume was not evident. EKC (10 micrograms/rat) when injected s.c. caused diuresis, but was ineffective as a diuretic when injected into the lateral ventricle. EKC was effective in blocking stimulation of vasopressin secretion caused by volume contraction. EKC also blocked vasopressin-stimulated water flow in the toad bladder, a model of the renal distal tubule and collecting duct. We propose that EKC is diuretic by virtue of inhibition of vasopressin secretion and attenuation of the ADH response in the kidney. Both of these actions may be mediated via opioid receptors responsive to kappa agonists and inaccessible from the cerebroventricle.