Dopamine fails to inhibit Na,H-exchanger in proximal tubules of obese Zucker rats.
Dopamine via the activation of D1-like receptors inhibits Na,K-ATPase and Na,H-exchanger and subsequently increases sodium excretion. We have previously reported that dopamine failed to inhibit Na,K-ATPase in the proximal tubules (PTs) of obese Zucker rats. The present study was designed to determine the effect of dopamine on Na,H-exchanger in PTs of lean and obese Zucker rats, and examine D1-like receptor-coupled signal transduction pathway mediating the inhibition of Na,H-exchanger. We found that dopamine inhibited Na,H-exchanger in the PTs of lean rats but this response was absent in obese rats. In brush border membranes, [3H]SCH 23390 binding revealed a approximately 45% reduction in D1-like receptor binding sites in obese compared to lean rats. Dopamine stimulated cAMP accumulation in PTs of lean but not in obese rats. Forskolin-mediated stimulation of cAMP was similar in lean and obese rats. Dopamine as well as forskolin and dibutyryl cAMP-mediated stimulation of protein kinase A (PKA) was reduced in PTs of obese compared to lean rats. The data suggest that reduction in D1-like receptor binding sites, defective coupling with signaling pathway and inability of PKA activation may be responsible for the failure of dopamine to inhibit Na,H-exchanger in PTs of obese rats. This phenomenon may contribute to an increase in sodium reabsorption and development of hypertension in obese Zucker rats.
Hussain
T
T
Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, TX 77204, USA.
Becker
M
M
Beheray
S
S
Lokhandwala
M F
MF
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology*; D006973:Hypertension / Q000209:etiology; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008871:Microvilli / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects* / Q000378:metabolism*
D017447:Receptors, Dopamine D1; D017923:Sodium-Hydrogen Exchangers; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine