D-1 dopamine receptor regulation of NHE3 during development in spontaneously hypertensive rats

To determine if the defective interactions among D-1-like receptors, G prot eins, and Na+/H+ exchanger 3 (NHE3) are consequences of hypertension, we st udied these interactions in rats, before (2-3 wk) and after (12 wk) the est ablishment of hypertension. To eliminate the confounding influence of secon d messenger action on D-1 receptor-NHE3 interaction, studies were performed in renal brush-border membranes (BBM) devoid of cytoplasmic second messeng ers. 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 spo ntaneously 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 inh ibitory effect of a D-1-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 D-1-li ke agonist, fenoldopam, on NHE3 activity in SHRs was not caused by increase d activity and binding of G beta gamma to NHE3 as has been reported in youn g WKY rats. Gsa mediates, in part, the inhibitory effect of D-1-like agonis ts on NHE3 activity. In WKY rats, fenoldopam increased G(s)alpha /NHE3 bind ing 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 Gsa bo und 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 D-1-like ago nists on NHE3 activity in SHRs (compared with WKY rats) precedes the develo pment of hypertension. This may be caused, in part, by a decreased interact ion between Gsa and NHE3 in BBM secondary to impaired D-1-like receptor fun ction.