DOPAMINE-1 AND DOPAMINE-2 MECHANISMS IN THE CONTROL OF RENAL-FUNCTION

Dopamine (DA), a catecholamine produced in the kidney, is a renal vasodilator and natriuretic substance, but its action at dopamine-1 (DA-1), dopamine-2 (DA-2) and α and β adrenergic receptors limits its effectiveness as a heuristic tool and pharmacologic agent. We have studied the effects of highly selective DA-l and DA-2 receptor agonists and antagonists in normal human subjects and experimental animals to determine the precise physiological role of renal dopamine at DA-1 and DA-2 receptors within the kidney. We studied fenoldopam, a selective DA-1 agonist, in normal human subjects in metabolic balances at high (300 mEq/day) and low (10 mEq/day) sodium (Na) intake. Selective DA-1 receptor stimulation during high Na intake resulted in renal vasodilation, natriuresis and diuresis in a sustained manner for 3 hours. The natriuresis was mediated by a reduction in Na reabsorption at both proximal and distal tubular sites. In contrast, during low Na intake, DA-1 receptor stimulation did not engender a natriuretic or diuretic response. Thus, sodium depletion may inhibit the function of renal tubular cells in response to DA-1 stimulation.DA-1 receptors are present in the medial layer of the renal vasculature, proximal tubule and cortical collecting duct; DA-2 receptors are localized to the glomerulus, the renal nerves surrounding renal blood vessels and possibly the renal vascular endothelium. We have performed studies in conscious dogs with indwelling renal arterial catheters to identify the physiological role of renal DA to DA-l and DA-2 receptors. Blockade of renal DA-l receptors with SCH-23390 produces a dose-dependent decrease in Na and water excretion without change in renal hemodynamic function. Blockade of renal DA-2 receptors with YM-09151 produces a dose-dependent increase in renal blood flow and glomerular filtration rate without alteration in renal tubular function. These changes are totally blocked with selective DA-1 (fenoldopam) and DA-2 (LY-171555) agonists, respectively. DA is a physiologically important paracrine substance. The compartmental localization within the kidney of DA production, release and action may play an important role in the specific paracrine action of DA. © 1990 by the American Journal of Hypertension, Ltd.