The Role of Dopamine-Metabolising Enzymes in Renal Sodium Handling. An Experimental Study in vivo

Abstract: Dopamine (DA) has been shown to act as an intrarenal natriuretic hormone and defects in the renal DA system have been associated with some forms of hypertension. How the DA activity is upregulated durin- increased sodium intake is, however, unknown. The present study addressed some aspects of the regulation and execution of DA-mediated natriuresis, with the main focus on the role of the DA-metabolising enzyme catechol-O-methyltransferase (COMT). COMT inhibition results in DA-induced natriuresis. The natriuretic response is mediated via the D1-like receptor and not the D2-like receptor and does not involve changes in renal haemodynamics, pointing to an effect on tubular sodium transport. MAO inhibition does not after sodium excretion. Furthermore, specific renal cortical COMT activity is reduced during partly D1-like receptor-mediated natriuresis, whereas MAO activity remains unchanged. The results suggest that the importance of MAO is negligible compared to COMT in regulating DA- mediated natriuresis in the rat. Systemic administration of a DA precursor only results in a modest increase in urinary sodium excretion in spite of a large increase in urinary DA excretion. These results indicate that DA metabolism is important in sodium homeostasis and that intrarenal DA activity is more likely regulated via DA metabolism and not primarily through a change in the systemic availability of the DA precursor. The natriuretic and haemodynamic effects of an elevation in DA activity were shown to depend on the route by which the elevation occurred. Intrarenally produced DA does not influence haemodynamics, whereas a DA agonist given systematically elicits an increase in cortical and outer medullary blood flow via vascular D1-like receptors. Cortical and outer medullary oxygen tension was not measurably altered during DA- induced natriuresis. In genetically modified mice it was shown that a reduced or absent COMT activity results in an inability to increase the renal DA activity and to produce normal natriuresis in response to sodium loading. In summary, the results from the present study suggests that COMT activity in the kidney plays an important role in the DA-mediated regulation of renal sodium excretion in response to sodium loading in rats and mice.