The dopaminergic and renin angiotensin systems interact to regulate blood pressure. Disruption of the D4 dopamine receptor gene in mice produces hypertension that is associated with increased renal AT1 receptor expression. We hypothesize that the D4 receptor can inhibit AT1 receptor expression and function in renal proximal tubules (RPTs) cells from Wistar-Kyoto (WKY) rats but the D4 receptor regulation of AT1 receptor is aberrant in RPT cells from spontaneously hypertensive rats (SHRs). The D4 receptor agonist, PD168077, decreased AT1 receptor protein expression in a time and concentration-dependent manner in WKY cells. By contrast, in SHR cells, PD168077 increased AT1 receptor protein expression. The inhibitory effect of D4 receptor on AT1 receptor expression in WKY cells was blocked by a calcium channel blocker, nicardipine, or calcium-free medium, indicating that calcium is involved in the D4 receptor-mediated signaling pathway. Angiotensin II increased Na+-K+ ATPase activity in WKY cells. Pretreatment with PD168077 decreased the stimulatory effect of angiotensin II on Na+-K+ ATPase activity in WKY cells. In SHR cells, the inhibitory effect of D4 receptor on angiotensin II-mediated stimulation of Na+-K+ ATPase activity was aberrant; pretreatment with PD168077 augmented the stimulatory effect of AT1 receptor on Na+-K+ ATPase activity in SHR cells. This was confirmed in vivo; pre-treatment with PD128077 for one week augmented the anti-hypertensive and natriuretic effect of losartan in SHRs but not in WKY rats. We suggest that an aberrant interaction between D4 and AT1 receptors may play a role in the abnormal regulation of sodium excretion in hypertension.
The dopaminergic and renin angiotensin systems interact to regulate blood pressure. Disruption of the D 4 dopamine receptor gene in mice produces hypertension that is associated with increased renal AT 1 receptor expression. We hypothesize that the D 4 receptor can inhibit AT 1 receptor expression and function in renal proximal tubules (RPTs) cells from Wistar-Kyoto (WKY) rats but the D 4 receptor regulation of AT 1 receptor is aberrant in RPT cells from spontaneously hypertensive rats (SHRs). The D 4 receptor agonist, PD168077, decreased AT 1 receptor protein expression in a time and concentration-dependent manner in WKY cells. By contrast, in SHR cells, PD168077 increased AT 1 receptor protein expression. The inhibitory effect of D 4 receptor on AT 1 receptor expression in WKY cells was blocked by a calcium channel blocker, nicardipine, or calcium-free medium, indicating that calcium is involved in the D 4 receptor-mediated signaling pathway. Angiotensin II increased Na + -K + ATPase activity in WKY cells. Pretreatment with PD168077 decreased the stimulatory effect of angiotensin II on Na + -K + ATPase activity in WKY cells. In SHR cells, the inhibitory effect of D 4 receptor on angiotensin II-mediated stimulation of Na + -K + ATPase activity was aberrant; pretreatment with PD168077 augmented the stimulatory effect of AT 1 receptor on Na + -K + ATPase activity in SHR cells. This was confirmed in vivo; pretreatment with PD128077 for one week augmented the anti-hypertensive and natriuretic effect of losartan in SHRs but not in WKY rats. We suggest that an aberrant interaction between D 4 and AT 1 receptors may play a role in the abnormal regulation of sodium excretion in hypertension.
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