D-1-like dopamine receptor activation and natriuresis by nitrocatechol COMT inhibitors

Background. In recent years, several nitmcatechol derivatives (tolcapone, e ntacapone, and nitecapone) have been developed and found to be highly selec tive and potent inhibitors of catechol-O-methyltransferase (COMT). More rec ently, natriuretic properties were described for two of these compounds (en tacapone and nitecapone), although this was not accompanied by enhanced uri nary excretion of dopamine. We hypothesized that nitrocatechol derivatives stimulate D-1-like dopamine receptors. Methods. Adult male Wistar rats were treated with a nitrocatechol COMT inhi bitor (entacapone, tolcapone, or nitecapone, 39 mg/kg, orally), and the uri nary excretion of dopamine and sodium was quantitated. The interaction of n itrocatechol derivatives with D-1-like receptors was evaluated by their abi lity to displace [H-3]-Sch23390 binding from membranes of rat renal cortex and cAMP production in opossum kidney (OK) cells. Results. Urinary excretion of sodium (mu mol/h) was markedly increased by a ll three nitrocatechol derivatives: vehicle, 55.0 +/- 5.6; entacapone, 98.4 +/- 9.3; tolcapone, 97.5 +/- 9.3; and nitecapone, 120.5 +/- 12.6. Pretreat ment with the selective, antagonist Sch 23390 (60 mug/kg) tsmpletely preven ted their natriuretic effects. Nitecapcane and tolcapone were equipotent (I C50, of 48 and 42 mu mol/L) and more potent than entacapone and dopamine (I C(50)s, of 107 and 279 mu mol/L) in displacing [H-3]-Sch23390 binding. In O K cells, all three nitrocatechol derivatives significantly increased cAMP a ccumulation and reduced Na+/H+ exchange and Na+,K+-ATPase activities, this being prevented by a blockade of D-1-like receptors. Conclusion. Stimulation of D-1-like dopamine receptors and inhibition of Na +/H+ exchange and Na+,K+-ATPase activities by nitrocatechol COMT inhibitors may contribute to natriuresis produced by these compountls.