Synergistic Effect of Uroguanylin and D(1) Dopamine Receptors on Sodium Excretion in Hypertension

BACKGROUND: Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl, indicating the existence of a gastro‐renal axis. As one of the major natriuretic hormones secreted by both the intestines and the kidney, we hypothesized that renal uroguanylin interacts with dopamine receptors to increase sodium excretion synergistically, an impaired interaction of which may be involved in the pathogenesis of hypertension. METHODS AND RESULTS: In Wistar‐Kyoto rats, the infusion of uroguanylin or fenoldopam (a D(1)‐like receptor agonist) induced natriuresis and diuresis. Although subthreshold dosages of uroguanylin or fenoldopam had no effect, the coinfusion of subthreshold dosages of those reagents significantly increased sodium excretion. The coinfusion of an antagonist against D(1)‐like receptors, SCH23390, or an antagonist against uroguanylin, 2‐methylthioadenosine triphosphate, prevented the fenoldopam‐ or uroguanylin‐mediated natriuresis and diuresis in Wistar‐Kyoto rats. However, the natriuretic effects of uroguanylin and fenoldopam were not observed in spontaneously hypertensive rats. The uroguanylin/D(1)‐like receptor interaction was also confirmed in renal proximal tubule cells. In renal proximal tubule cells from Wistar‐Kyoto rats but not spontaneously hypertensive rats, stimulation of either D(1)‐like receptors or uroguanylin inhibited Na(+)‐K(+)‐ATPase activity, an effect that was blocked in the presence of SCH23390 or 2‐methylthioadenosine triphosphate. In renal proximal tubule cells from Wistar‐Kyoto rats, guanylyl cyclase C receptor (uroguanylin receptor) and D(1) receptor coimmunoprecipitated, which was increased after stimulation by either uroguanylin or fenoldopam; stimulation of one receptor increased renal proximal tubule cell membrane expression of the other. CONCLUSIONS: These data suggest that there is synergism between uroguanylin and D(1)‐like receptors to increase sodium excretion. An aberrant interaction between the renal uroguanylin and D(1)‐like receptors may play a role in the pathogenesis of hypertension.