Dopamine(1) receptor, G(salpha), and Na(+)-H(+) exchanger interactions in the kidney in hypertension.
The ability of dopamine(1) (D(1)) 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 D(1) receptor, G(salpha), or effector proteins. The coupling of the D(1) receptor to G(salpha) and NHE3 was studied in renal brush border membranes (BBM), devoid of cytoplasmic second messengers. D(1) receptor, G(salpha), and NHE3 expressions were similar in SHR and their normotensive controls, Wistar-Kyoto rats (WKY). Guanosine-5'-O:-(3-thiotriphosphate) (GTPgammaS) decreased NHE activity and increased NHE3 linked with G(salpha) similarly in WKY and SHR, indicating normal G(salpha) and NHE3 regulation in SHR. However, D(1) agonists increased NHE3 linked with G(salpha) in WKY but not in SHR, and the inhibitory effects of D(1) agonists on NHE activity were less in SHR than in WKY. Moreover, GTPgammaS enhanced the inhibitory effect of D(1) agonist on NHE activity in WKY but not in SHR, suggesting an uncoupling of the D(1) receptor from G(salpha)/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 D(1) receptor function in renal proximal tubules in SHR is proximal to G(salpha)/effectors and presumably at the receptor level. The mechanism(s) responsible for the uncoupling of the D(1) receptor from G proteins remains to be determined. Because the primary structure of the D(1) receptor is not different between normotensive and hypertensive rats, differences in D(1) receptor posttranslational modification are possible.
Xu
J
J
Department of Pediatrics, Georgetown University Medical Center, Washington, DC 20007, USA.
Li
X X
XX
Albrecht
F E
FE
Hopfer
U
U
Carey
R M
RM
Jose
P A
PA
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018818:Fenoldopam / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D011233:Precipitin Tests; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013045:Species Specificity
D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D017923:Sodium-Hydrogen Exchangers; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C067113:SK&F 81297; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D018818:Fenoldopam