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(Hypertension. 2000;36:395.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Dopamine₁ Receptor, G_s, and Na⁺-H⁺ Exchanger Interactions in the Kidney in Hypertension

Jing Xu; Xiao Xi Li; Frederick E. Albrecht; Ulrich Hopfer; Robert M. Carey; Pedro A. Jose

From the Departments of Pediatrics (J.X., X.X.L., F.E.A., P.A.J.) and Physiology and Biophysics (F.E.A., P.A.J.), Georgetown University Medical Center, Washington, DC; Department of Physiology, Case Western Reserve School of Medicine, Cleveland, Ohio (U.H.); and Department of Medicine, University of Virginia Health Sciences Center, Charlottesville (R.M.C.).

Correspondence to Pedro A. Jose, MD, PhD, Department of Pediatrics, Georgetown University Medical Center, 3800 Reservoir Rd NW, Washington, DC 20007. E-mail josep{at}gunet.georgetown.edu

Abstract—The ability of dopamine₁ (D₁) receptors to inhibit luminal Na⁺-H⁺ exchanger (NHE) activity in renal proximal tubules and induce a natriuresis is impaired in spontaneously hypertensive rats (SHR). However, it is not clear whether the defect is at the level of the D₁ receptor, G_s, or effector proteins. The coupling of the D₁ receptor to G_s and NHE3 was studied in renal brush border membranes (BBM), devoid of cytoplasmic second messengers. D₁ receptor, G_s, and NHE3 expressions were similar in SHR and their normotensive controls, Wistar-Kyoto rats (WKY). Guanosine-5'-O-(3-thiotriphosphate) (GTPS) decreased NHE activity and increased NHE3 linked with G_s similarly in WKY and SHR, indicating normal G_s and NHE3 regulation in SHR. However, D₁ agonists increased NHE3 linked with G_s in WKY but not in SHR, and the inhibitory effects of D₁ agonists on NHE activity were less in SHR than in WKY. Moreover, GTPS enhanced the inhibitory effect of D₁ agonist on NHE activity in WKY but not in SHR, suggesting an uncoupling of the D₁ receptor from G_s/NHE3 in SHR. Similar results were obtained with the use of immortalized renal proximal tubule cells from WKY and SHR. We conclude that the defective D₁ receptor function in renal proximal tubules in SHR is proximal to G_s/effectors and presumably at the receptor level. The mechanism(s) responsible for the uncoupling of the D₁ receptor from G proteins remains to be determined. Because the primary structure of the D₁ receptor is not different between normotensive and hypertensive rats, differences in D₁ receptor posttranslational modification are possible.

Key Words: dopamine • receptors, dopamine • G protein • rats, inbred SHR