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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 angiotensin type 1 (AT1) receptor expression. We hypothesize that the D4 receptor can inhibit AT1 receptor expression and function in renal proximal tubule cells from Wistar-Kyoto (WKY) rats, but the D4 receptor regulation of AT1 receptor is aberrant in renal proximal tubule 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; pretreatment with PD128077 for 1 week augmented the antihypertensive and natriuretic effect of losartan in SHRs but not in WKY rats. We suggest that an aberrant interaction between DD4 and AT1 receptors may play a role in the abnormal regulation of sodium excretion in hypertension. [ABSTRACT FROM AUTHOR]

G-protein-coupled receptor kinase 4 (GRK4) gene variants, via impairment of renal dopamine receptor and enhancement of renin-angiotensin system functions, cause sodium retention and increase blood pressure. Whether GRK4 and the angiotensin type 1 receptor (AT1R) interact in the aorta is not known. We report that GRK4 is expressed in vascular smooth muscle cells of the aorta. Heterologous expression of the GRK4 variant 142V in A10 cells increased AT1R protein expression and AT1R-mediated increase in intracellular calcium concentration. The increase in AT1R expression was related to an increase in AT1R mRNA expression via the NF-κB pathway. As compared with control, cells expressing GRK4γ 142V had greater NF-κ3 activity with more NF-κ3 bound to the AT1R promoter. The increased AT1R expression in cells expressing GRK4γ 142V was also associated with decreased AT1R degradation, which may be ascribed to lower ATIR phosphorylation. There was a direct interaction between GRK4γ and AT1R that was decreased by GRK4γ 142V. The regulation of AT1R expression by GRK4γ 142V in A10 cells was confirmed in GRK4γ 142V transgenic mice; AT1R expression was higher in the aorta of GRK4γ 142V transgenic mice than control GRK4γ wild-type mice. Angiotensin H-mediated vasoconstriction of the aorta was also higher in GRKγ 142V than in wild-type transgenic mice. This study provides a mechanism by which GRK4γ via regulation of arterial AT1R expression and function, participates in the pathogenesis of conduit vessel abnormalities in hypertension. [ABSTRACT FROM AUTHOR]

Oral NaC1 produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaC1. Gastrin is the major gastrointestinal hormone taken up by renal proximal tubule (RPT) cells. We hypothesized that renal gastrin and dopamine receptors interact to synergistically increase sodium excretion, an impaired interaction of which may be involved in the pathogenesis of hypertension. In Wistar-Kyoto rats, infusion of gastrin induced natriuresis and diuresis, which was abrogated in the presence of a gastrin (cholecystokinin B receptor [CCKBR]; CI-988) or a D1-like receptor antagonist (SCH23390). Similarly, the natriuretic and diuretic effects of fenoldopam, a D1-like receptor agonist, were blocked by SCH23390, as well as by CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats. The gastrin/D1-like receptor interaction was also confirmed in RPT cells. In RPT cells from Wistar-Kyoto but not spontaneously hypertensive rats, stimulation of either Dclike receptor or gastrin receptor inhibited Na+-K+-ATPase activity, an effect that was blocked in the presence of SCH23390 or CI-988. In RPT cells from Wistar-Kyoto and spontaneously hypertensive rats, CCKBR and D1 receptor coimmunoprecipitated, which was increased after stimulation of either D1 receptor or CCKBR in RFF cells from Wistar-Kyoto rats; stimulation of one receptor increased the RPT cell membrane expression of the other receptor, effects that were not observed in spontaneously hypertensive rats. These data suggest that there is a synergism between CCKBR and D1-like receptors to increase sodium excretion. An aberrant interaction between the renal CCKBR and D1-like receptors (eg, D1 receptor) may play a role in the pathogenesis of hypertension. [ABSTRACT FROM AUTHOR]