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Am J Physiol Regul Integr Comp Physiol 280: R1650-R1656, 2001;
0363-6119/01 $5.00
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Vol. 280, Issue 6, R1650-R1656, June 2001

D1 dopamine receptor regulation of NHE3 during development in spontaneously hypertensive rats

Xiao Xi Li1, Jing Xu1, Shaopeng Zheng1, Frederick E. Albrecht1,2, Jean E. Robillard3, Gilbert M. Eisner4, and Pedro A. Jose1,2

Departments of 1 Pediatrics, 2 Physiology and Biophysics, and 4 Medicine, Georgetown University Medical Center, Washington, District of Columbia 20007; and 3 Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan 48109

To determine if the defective interactions among D1-like receptors, G proteins, and Na+/H+ exchanger 3 (NHE3) are consequences of hypertension, we studied these interactions in rats, before (2-3 wk) and after (12 wk) the establishment of hypertension. To eliminate the confounding influence of second messenger action on D1 receptor-NHE3 interaction, studies were performed in renal brush-border membranes (BBM) devoid of cytoplasmic second messengers. NHE3 activity increased with age in Wistar-Kyoto (WKY) rats (3 wk = 1.48 ± 0.39, n = 13; 12 wk = 2.83 ± 0.15, n = 16, P < 0.05) but not in spontaneously hypertensive rats (SHRs; 3 wk = 2.52 ± 0.37, n = 11; 12 wk = 2.81 ± 0.20, n = 16). D1 receptor protein tended to decrease, whereas NHE3 protein tended to increase with age in both WKY and SHRs. However, the inhibitory effect of a D1-like agonist, SKF-81297, on NHE3 activity increased with age in WKY rats (3 wk = -40.7 ± 5.3%, n = 10, 12 wk = -58.7 ± 4.6%, n = 12, P < 0.05) but not in SHRs (3 wk = -27.6 ± 5.9%, n = 11, 12 wk = -25.1 ± 3.2%, n = 11). The decreased inhibitory effect of another D1-like agonist, fenoldopam, on NHE3 activity in SHRs was not caused by increased activity and binding of Gbeta gamma to NHE3 as has been reported in young WKY rats. Gsalpha mediates, in part, the inhibitory effect of D1-like agonists on NHE3 activity. In WKY rats, fenoldopam increased Gsalpha /NHE3 binding to the same extent in 2-wk-old (1.5-fold, n = 4) and adult (1.5-fold, n = 4) rats. In contrast, in SHRs, fenoldopam decreased the amount of Gsalpha bound to NHE3 in 2-wk-old SHRs and had no effect in 4-wk-old and adult SHRs. These studies indicate that the decreased inhibitory effect of D1-like agonists on NHE3 activity in SHRs (compared with WKY rats) precedes the development of hypertension. This may be caused, in part, by a decreased interaction between Gsalpha and NHE3 in BBM secondary to impaired D1-like receptor function.

brush-border membrane; G protein; fenoldopam; sodium/hydrogen exchanger 3


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