Dopamine fails to inhibit renal tubular sodium pump in hypertensive rats.

Abstract

We have previously reported that dopamine-1 receptor-mediated activation of phospholipase C is diminished in renal cortical slices of adult spontaneously hypertensive rats. To determine the potential consequences of this phenomenon, we performed the present studies in which renal proximal tubule suspensions obtained from spontaneously hypertensive and Wistar-Kyoto rats of 10-12 weeks of age were used. The tubule suspensions were incubated with dopamine in the presence or absence of dopamine receptor antagonists, and sodium, potassium adenosine trisphosphatase (sodium pump) activity was measured as the ouabain-sensitive adenosine trisphosphate hydrolysis. We found that dopamine produced a concentration-related inhibition of sodium pump activity in the normotensive rats but not in the hypertensive rats. Dopamine-induced inhibition of sodium pump activity in the normotensive rats was abolished by the phospholipase C inhibitor U-73122 or the protein kinase C inhibitor sphingosine, suggesting the involvement of a phospholipase C-coupled protein kinase C pathway in this response. Dopamine-induced inhibition in the normotensive rats was attenuated by the dopamine-1 receptor antagonist SCH 23390 but not by the dopamine-2 receptor antagonist domperidone. To identify possible sites of defect in dopamine-1 receptor-coupled signaling pathways in the hypertensive rats, we incubated the proximal tubules with phorbol 12,13-dibutyrate or the synthetic diacylglycerol analogue l-oleoyI-2-acetyl-rac-glycerol. The results showed that both compounds inhibited sodium pump activity as effectively in the hypertensive as in the normotensive rats, suggesting that the protein kinase C-coupled sodium pump pathway was not defective in the hypertensive animals. Failure of dopamine to inhibit sodium pump activity in the hypertensive rats could not be due to a defective dopamine-1 receptor adenylate cyclase coupling, because dopamine was still unable to inhibit sodium pump activity in the presence of dibutyryl cyclic adenosine monophosphate or forskolin. These results show that dopamine failed to inhibit sodium pump activity in the proximal tubules of adult hypertensive rats, which may be mainly due to a defect in the dopamine-1 receptor-mediated signal transduction pathway. The site of this defect is most likely proximal to the activation of protein kinase C and may involve a defect in the dopamine-1 receptor phospholipase C coupling process. (Hypertension 1993;21:364-372) KEY WORDS • receptors, dopamine • dopamine • sodium • phospholipase C • adenosine trisphosphatase, sodium, potassium A bnormal renal sodium handling has been known / \ to be one of the major factors involved in the -Z A . initiation and maintenance of high blood pressure in several models of hypertension, including genetic hypertension. 1 -2 Endogenous kidney dopamine plays an important role in regulation of renal sodium excretion, so it has been proposed that impaired renal sodium handling in spontaneously hypertensive rats (SHR) may partly be due to a malfunction or a d...

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