Renal dopamine receptors and pre- 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 125I-Sch 23982 at a high-affinity site (KiH = 1.8 +/- 0.8 x 10(-8) M) and a low-affinity site (KiL = 7.6 +/- 1.1 x 10(-5) M, n = 6). Na+ (150 mM) or Gpp(NH)p (10(-4) M) converted KiH to KiL. NEM, which alkylates sulfhydryl groups, also converted all the binding to KiL; this effect could be prevented by prior treatment with 10(-4) M fenoldopam. In contrast, in SHR, fenoldopam detected only a KiL (7.8 +/- 1.4 x 10(-5) M, n = 6). Neither Na+, Gpp(NH)p, nor NEM had any effect on KiL. 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pathology, University of Virginia Medical Center, Charlottesville 22908.
A
A
Horiuchi
F E
FE
Albrecht
G M
GM
Eisner
P A
PA
Jose
R A
RA
Felder
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D018818:Fenoldopam; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR / Q000378:metabolism*; D011921:Rats, Inbred WKY; D011954:Receptors, Dopamine / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers; D013873:Thionucleotides / Q000494:pharmacology
D002352:Carrier Proteins; D015259:Dopamine Agents; D011954:Receptors, Dopamine; D017923:Sodium-Hydrogen Exchangers; D013873:Thionucleotides; D006165:Guanylyl Imidodiphosphate; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D012964:Sodium; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D018818:Fenoldopam; D005033:Ethylmaleimide