Arguments against a mediating role of the adenylate cyclase--cyclic AMP system in the ototoxic action of loop diuretics.

Abstract

Previous studies in our laboratory have indicated that adenylate cyclase of the stria vascularis is strongly inhibited in vitro by ethacrynic acid and furosemide. In order to test whether the in vitro effects upon the enzyme are also present under in vivo conditions, ethacrynic acid was perfused perilymphatically for 15 min and 20 min at a concentration of 10(-3) M. Cyclic AMP of the stria vascularis was reduced by 27% and 34%, respectively, but ATP also declined significantly, suggesting unspecific effects. When ethacrynic acid was applied intravenously at a dosage of 50 mg/kg, and the endolymphatic potential allowed to decline to -10mV, no significant changes in cyclic AMP and ATP were seen. The absence of effects upon cyclic AMP in the early stage of systemic intoxication with ethacrynic acid is strong evidence against a mediating role of adenylate cyclase in the ototoxic action of ethacrynic acid. When a bolus of 3 x 10(-2) M furosemide was applied intra-arterially the endolymphatic potential declined at the exceedingly rapid rate of about 10 mV/sec, strongly suggesting that the action of the drug takes place in the vicinity of the capillaries of the stria vascularis. In view of the proposition that adenylate cyclase appears to be located primarily at eh luminal aspect of the stria vascularis, this constitutes further evidence against a role of the enzyme in the mediation of the specific ototoxic effects of loop diuretics. Other recent evidence against a mediatory role of the adenylate cyclase--cyclic AMP system is discussed.