Diminished natriuretic response to dopamine in old rats is due to an impaired D1-like receptor-signaling pathway.
BACKGROUND
Dopamine (DA) causes natriuresis and diuresis, which results from activation of D1-like receptor (D1R) located on proximal tubules. Earlier, we reported that DA failed to inhibit Na,K-ATPase in proximal tubules of old Fischer 344 rats. The present study was designed to investigate the functional consequence of this phenomenon.


METHODS
Measurements of the functional (natriuretic and diuretic) response to intravenously infused DA and SKF 38393 (D1R agonist) in adult (6 month) and old (24 month) Fischer 344 rats were taken. Biochemical measurements were carried out to determine the potential defects in D1R and its signaling pathway in proximal tubules of old rats.


RESULTS
We found that intravenous infusion of DA and SKF 38393 caused natriuresis and diuresis in adult rats, but this response was blunted in old rats. In the isolated proximal tubules, DA and SKF 38393 inhibited Na,H-exchanger (NHE) in adult rats; however, this inhibition was attenuated in old rats. Radioligand binding revealed approximately 46% reduction in D1R binding sites in brush border membranes (BBMs) in old compared with adult rats. SKF 38393 stimulated [35S]GTPgammaS binding in BBM in adult rats, but not in old rats, suggesting an impaired D1R-G protein coupling. DA and SKF 38393 stimulated adenylyl cyclase (AC) activity in adult but not in the old rats. Forskolin and NaF stimulated AC activity in a comparable manner in adult and old rats, indicating no defect in AC and G proteins. DA and SKF 38393 failed to stimulate protein kinase A (PKA) activity in proximal tubules of old rats. Dibutyryl-cAMP-mediated PKA activation was also absent in old rats.


CONCLUSIONS
A decrease in D1R binding sites, a coupling defect with G proteins, and a defect in PKA activation lead to diminished DA-mediated inhibition of NHE in old rats, which may contribute to the blunted natriuretic response to DA in these animals.
Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, TX 77204-5511, USA.
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Beheray
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Kansra
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Hussain
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MF
Lokhandwala
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D006706:Homeostasis / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000201:enzymology; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000032:analysis / Q000378:metabolism; D013462:Sulfur Radioisotopes; D014316:Tritium
D002316:Cardiotonic Agents; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D017923:Sodium-Hydrogen Exchangers; D013462:Sulfur Radioisotopes; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D012964:Sodium; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D004298:Dopamine