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(Hypertension. 2003;41:1353.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Dopamine-Mediated Inhibition of Renal Na,K-ATPase Is Reduced by Insulin

From the Heart and Kidney Institute, University of Houston, Houston, Tex.

Correspondence to Dr Mustafa F. Lokhandwala, College of Pharmacy, University of Houston, Houston, TX 77204. E-mail mlokandwala{at}uh.edu

Recently we have reported that rosiglitazone treatment of obese Zucker rats reduced plasma insulin and restored the ability of dopamine to inhibit Na,K-ATPase (NKA) in renal proximal tubules. The present study was performed to test the hypothesis that a chronic increase in levels of insulin causes a decrease in expression of the D1 receptor and its uncoupling from G proteins, which may account for the diminished inhibitory effect of dopamine on NKA in obese Zucker rats. We conducted experiments in primary proximal tubule epithelial cells obtained from Sprague-Dawley rat kidneys. These cells at 80% to 90% confluence were pretreated with insulin (100 nmol/L for 24 hours) in growth factor–/serum-free medium. SKF-38393, a D1 receptor agonist, inhibited NKA activity in untreated cells, but the agonist failed to inhibit enzyme activity in insulin-pretreated cells. Basal NKA activity was similar in untreated and insulin-pretreated cells. Measurement of D1 receptors in the plasma membranes revealed that [³H]SCH-23390 binding, a D1 receptor ligand, as well as D1 receptor protein abundance, was significantly reduced in insulin-pretreated cells compared with untreated cells. SKF-38393 (10 µmol/L) elicited significant stimulation of [³⁵S]GTPS binding in the membranes from control cells, suggesting that the D1 receptor–G protein coupling was intact. However, the stimulatory effect of SKF-38393 was absent in membranes from insulin-pretreated cells. We suggest that chronic exposure of cells to insulin causes both the reduction in D1 receptor abundance and its uncoupling from G proteins. These phenomena might account for the diminished inhibitory effect of dopamine on NKA activity in hyperinsulinemic rats.

Key Words: dopamine • insulin • Na⁺-K⁺-transporting ATPase • receptors, dopamine • G proteins

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