RENAL DOPAMINE-RECEPTORS AND PREMEDIATED AND POST-CAMP-MEDIATED NA+ TRANSPORT DEFECT IN SPONTANEOUSLY HYPERTENSIVE RATS

We have reported defective coupling of the renal tubular DA1 dopamine receptor to adenylyl cyclase in both the spontaneously hypertensive rat (SHR) and the Dahl salt-sensitive rat. Since Na+, 5'-guanyl imidodiphosphate [Gpp(NH)p], and N-ethylmaleimide (NEM) reduce agonist affinity for brain D1 dopamine receptors, we compared the effects of these agents on agonist affinity in proximal tubules from SHR and its normotensive control, the Wistar-Kyoto rat (WKY), to delineate further the site of the DA1-adenylyl cyclase coupling defect. In WKY, the D1/DA1 agonist, fenoldopam, competed for I-125-Sch 23982 at a high-affinity site (K(i H) = 1.8 +/- 0.8 x 10(-8) M) and a low-affinity site (K(i L) = 7.6 +/- 1.1 x 10(-5) M, n = 6). Na+ (150 mM) or Gpp(NH)p (10(-4) M) converted K(i H) to K(i L). NEM, which alkylates sulfhydryl groups, also converted all the binding to K(i L); this effect could be prevented by prior treatment with 10(-4) M fenoldopam. In contrast, in SHR, fenoldopam detected only a K(i L) (7.8 +/- 1.4 x 10(-5) M, n = 6). Neither Na+, Gpp(NH)p, nor NEM had any effect on K(i L). To study a functional expression of these binding sites, the effect of 5 x 10(-5) M fenoldopam or 8-(chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8-CPT-cAMP) on Na+/H+ exchange activity in proximal tubular brush-border membrane vesicles was tested. In WKY, the inhibitory effects of these agents on the exchanger increased with the age of the rat. In SHR, fenoldopam did not inhibit the exchanger at any age; 8-CPT-cAMP had an effect in the young but not in the old SHR. These studies suggest that the proximal tubule of the SHR has a defective DA1 receptor. The resistance to the effect of D1/DA1 agonists on Na+ transport in the SHR may be due to decreased cAMP production as well as a post-cAMP defect that is acquired with maturation.