Abstract
<h3>Objective</h3> The dopaminergic and renin angiotensin systems interact to regulate blood pressure. Disruption of the D<sub>4</sub> dopamine receptor gene in mice produces hypertension that is associated with increased renal AT<sub>1</sub> receptor expression. We hypothesise that the D<sub>4</sub> receptor can inhibit AT<sub>1</sub> receptor expression and function in renal proximal tubules (RPTs) cells from Wistar-Kyoto (WKY) rats but the D<sub>4</sub> receptor regulation of AT<sub>1</sub> receptor is aberrant in RPT cells from spontaneously hypertensive rats (SHRs). <h3>Methods</h3> Immortalised RPT cells from WKY and SHRs were treated by The D<sub>4</sub> receptor agonist, PD168077 to determine the AT<sub>1</sub> receptor protein expression and Na<sup>+</sup>-K<sup>+</sup> ATPase activity, and treated by calcium channel blocker, nicardipine to determine the signalling molecule. Rats were treated <i><i>in vivo</i></i> by D<sub>4</sub> receptor agonist and losartan to obverse the anti-hypertensive and natriuretic effect. <h3>Results</h3> The D<sub>4</sub> receptor agonist, PD168077, <b><i>decreased</i></b> AT<sub>1</sub> receptor protein expression in a time (0–30 hrs)- and concentration (10<sup>–9</sup>–10<sup>–5</sup>M)-dependent manner in WKY RPT cells. By contrast, in SHR cells, PD168077 (10<sup>–6</sup>M) <b>increased</b> AT<sub>1</sub> receptor protein expression. The inhibitory effect of D<sub>4</sub> receptor on AT<sub>1</sub> receptor expression in WKY RPT cells was blocked by a calcium channel blocker, nicardipine (10<sup>–6</sup>M), or calcium-free medium, indicating that calcium is involved as a signalling molecule in the D<sub>4</sub> receptor-mediated signalling pathway. Angiotensin II (10<sup>–11</sup>M) increased Na<sup>+</sup>-K<sup>+</sup> ATPase activity in WKY cells. Pretreatment with PD168077 (10<sup>–6</sup>M/24hrs) decreased the stimulatory effect of angiotensin II on Na<sup>+</sup>-K<sup>+</sup> ATPase activity in WKY cells. However, in SHR cells, the inhibitory effect of D<sub>4</sub> receptor on angiotensin II-mediated stimulation of Na<sup>+</sup>-K<sup>+</sup> ATPase activity was aberrant; pretreatment with D<sub>4</sub> receptor agonist augmented the stimulatory effect of AT<sub>1</sub> receptor on Na<sup>+</sup>-K<sup>+</sup> ATPase activity in SHR cells. This was confirmed in <i><i>in vivo</i></i> studies; pre-treatment with PD128077 for one week augmented the anti-hypertensive and natriuretic effect of losartan in SHRs but not in WKY rats. <h3>Conclusions</h3> We suggest that an aberrant interaction between D<sub>4</sub> and AT<sub>1</sub> receptors may play a role in the abnormal regulation of sodium excretion and blood pressure in hypertension.
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