INHIBITION OF COMT INDUCES DOPAMINE-DEPENDENT NATRIURESIS AND INHIBITION OF PROXIMAL TUBULAR NA-ATPASE(,K+)

The enzyme catechol-O-methyltransferase (COMT), which plays an importa nt role for dopamine metabolism, is abundantly expressed in the kidney . To test whether the natriuretic effects of dopamine may be related t o the rate of dopamine metabolism, rats were treated with nitecapone, a peripheral inhibitor of COMT. Nitecapone, given by gavage, induced a highly significant (5.6-fold) increase in sodium excretion, which was associated with an inhibition of the Na+,K+-ATPase activity in both t he proximal convoluted and proximal straight tubules (PCT and PST, res pectively). These effects were completely abolished if the rats were a lso treated with a specific dopamine 1 antagonist, SCH 23390. Furtherm ore, the natriuretic effect of nitecapone was also observed in rats on a high salt diet. The kidney-specific pro-drug to dopamine, glu-dopa, induced a significant, but less pronounced increase in urinary sodium excretion, associated with a dopamine-dependent inhibition of the Na,K+-ATPase activity in the PCT but not in the PST. Nitecapone and glu- dopa had an additive natriuretic effect. It is concluded that COMT pla ys an important role in determining the natriuretic effects of the ren al dopamine system.