D1-like dopamine receptor activation and natriuresis by nitrocatechol COMT inhibitors

Abstract

Background. In recent years, several nitrocatechol derivatives (tolcapone, entacapone, and nitecapone) have been developed and found to be highly selective and potent inhibitors of catechol-O-methyltransferase (COMT). More recently, natriuretic properties were described for two of these compounds (entacapone and nitecapone), although this was not accompanied by enhanced urinary excretion of dopamine. We hypothesized that nitrocatechol derivatives stimulate D1-like dopamine receptors. Methods. Adult male Wistar rats were treated with a nitrocatechol COMT inhibitor (entacapone, tolcapone, or nitecapone, 30 mg/kg, orally), and the urinary excretion of dopamine and sodium was quantitated. The interaction of nitrocatechol derivatives with D1-like receptors was evaluated by their ability to displace [3H]-Sch23390 binding from membranes of rat renal cortex and cAMP production in opossum kidney (OK) cells. Results. Urinary excretion of sodium (μmol/h) was markedly increased by all three nitrocatechol derivatives: Vehicle, 55.0 ± 5.6; entacapone, 98.4 ± 9.3; tolcapone, 97.5 ± 9.3; and nitecapone, 120.5 ± 12.6. Pretreatment with the selective D1 antagonist Sch 23390 (60 μg/kg) completely prevented their natriuretic effects. Nitecapone and tolcapone were equipotent (IC50s of 48 and 42 μmol/L) and more potent than entacapone and dopamine (IC50s of 107 and 279 μmol/L) in displacing [3H]-Sch23390 binding. In OK cells, all three nitrocatechol derivatives significantly increased cAMP accumulation and reduced Na+/H+ exchange and Na+, K+-ATPase activities, this being prevented by a blockade of D1-like receptors. Conclusion. Stimulation of D1-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 compounds. © 2001 Elsevier Science Ltd. All rights reserved.