Antagonism of metergoline on the diuretic effect of cyclazocine and U-50488 drugs with a kappa agonist activity.

In rats receiving a normal saline load of 2.5 ml/100 g, sc, (moderately hydrated rats), injections of the serotonin (5-HT) antagonist, metergoline (0.25-1-4 mg/kg), resulted in a dose-dependent decrease in the urine output induced by a dose of 8 mg/kg of cyclazocine (a benzomorphan derivative, mixed kappa and sigma agonist) at the 2-h time period. The antagonist effect of metergoline (1 mg/kg) on cyclazocine doses ranging from 0.25 to 8 mg/kg, was observed only at 2 mg/kg higher doses. Other 5-HT receptor blockers, methysergide, pizotifen, cyproheptadine, caused a significant degree of antagonism. In rats receiving a saline load and a water load of 5.5 ml/100 g, ip (hyperhydrated rats), metergoline (1 mg/kg) completely antagonized the diuretic effect of cyclazocine (8 mg/kg) at the 4-h and 5-h time periods. Similarly, metergoline (1 and 4 mg/kg) administered in moderately hydrated rats, markedly decreased at the 2-h time period, the urine output produced by 5 mg/kg of U-50488 (a non benzomorphan derivative, highly selective kappa agonist), and in hyperhydrated rats, completely suppressed, at the 4-h and 5-h time periods the drug-induced diuresis. Metergoline administered alone had no effect on urine output in moderately hydrated rats or in hyperhydrated rats. These results suggest the hypothesis that 5-HT may be involved in the complex mechanisms of kappa agonist-induced diuresis in rats.