ALTERED ARACHIDONIC-ACID METABOLISM CONTRIBUTES TO THE FAILURE OF DOPAMINE TO INHIBIT NA-ATPASE IN KIDNEY OF SPONTANEOUSLY HYPERTENSIVE RATS(,K+)

Dopamine decreases tubular sodium reabsorption in part by inhibition o f Na+,K+-ATPase activity in renal proximal tubules. The signaling mech anism involved in dopamine-mediated inhibition of Na+,K+-ATPase is kno wn to be defective in spontaneously hypertensive animals. The present study was designed to evaluate the role of phospholipase A2 (PLA2) and its metabolic pathway in dopamine-induced inhibition of Na+,K+-ATPase in renal proximal tubules from Wistar-Kyoto (WKY) rats and spontaneou sly hypertensive rats (SHR). Renal proximal tubular suspensions were p repared and Na+,K+-ATPase activity was measured as ouabain-sensitive a denosine triphosphate hydrolysis. Dopamine inhibited Na+,K+-ATPase act ivity in a concentration (1 nM - 10 mu M)-dependent manner in WKY rats while it failed to inhibit the enzyme activity in SHR. Dopamine (10 m u M)-induced inhibition of Na+,K+-ATPase activity in WKY rats was sign ificantly blocked by mepacrine (10 mu M), a PLA2 inhibitor, suggesting the involvement of PLA2 in dopamine-mediated inhibition of Na+,K+-ATP ase. Arachidonic acid (a product released by PLA2 action) inhibited Na +,K+-ATPase in a concentration-dependent (1-100 mu M) manner in WKY ra ts while the inhibition in SHR was significantly attenuated (IC50: 7.5 and 80 mu M in WKY rats and SHR, respectively). Furthermore, lower co ncentrations of arachidonic acid stimulated (30% at 1 mu M) Na+,K+-ATP ase activity in SHR. This suggests a defect in the metabolism of arach idonic acid in SHR. Proadifen (10 mu M), an inhibitor of cytochrome P- 450 monoxygenase (an arachidonic acid metabolizing enzyme) significant ly blocked the inhibition produced by arachidonic acid in WKY rats and abolished the difference in arachidonic acid inhibition of Na+,K+-ATP ase between WKY rats and SHR. These data suggest that PLA2 is involved in dopamine-induced inhibition of Na+,K+-ATPase and altered arachidon ic acid metabolism may contribute to reduced dopaminergic inhibition o f Na+,K+-ATPase activity in spontaneously hypertensive rats.