Dopamine fails to inhibit Na,H-exchanger in proximal tubules of obese Zucker rats

Dopamine via the activation of D-1-like receptors inhibits Na,K-ATPase and Na,H-exchanger and subsequently increases sodium excretion. We have previou sly reported that dopamine failed to inhibit Na,K-ATPase in the proximal tu bules (PTs) of obese Zucker rats. The present study was designed to determi ne the effect of dopamine on Na,H-exchanger in PTs of lean and obese Zucker rats, and examine D-1-like receptor-coupled signal transduction pathway me diating 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 obes e rats. In brush border membranes, [H-3] SCH 23390 binding revealed a simil ar to 45% reduction in Di-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 stimu lation of protein kinase A (PKA) was reduced in PTs of obese compared to le an rats. The data suggest that reduction in D-1-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 i n PTs of obese rats. This phenomenon may contribute to an increase in sodiu m reabsorption and development of hypertension in obese Zucker rats.