Role of 20-HETE in D1/D2 dopamine receptor synergism resulting in the inhibition of Na⁺-K⁺-ATPase activity in the proximal tubule

Abstract

Previous studies propose 20-hydroxyeicosatetraenoic acid (20-HETE), a major arachidonic acid metabolite of cytochrome P-450 (CYP), as a possible mediator of Na(+)-K(+)-ATPase inhibition by dopamine (DA). The aim of this study was to investigate the intracellular mechanisms involved in this effect and to elucidate the DA receptor associated with the 20-HETE pathway in the rat kidney. DA (10(-5) M) inhibited Na(+)-K(+)-ATPase activity in microdissected tubular segments to 59.4 +/- 3.8% of control activity. This response was suppressed by the CYP4A inhibitor 17-octadecynoic acid (10(-6) M), which had no effect per se, thus confirming the participation of CYP arachidonic acid metabolites in DA-induced Na(+)-K(+)-ATPase inhibition. We next examined whether 20-HETE is involved in the signaling pathways triggered by either D(1) or D(2) receptors. Neither fenoldopam nor quinpirole (D(1) and D(2) agonists, respectively, both 10(-5) M) modified Na(+)-K(+)-ATPase activity when tried alone. However, coincubation of a threshold concentration of 20-HETE (10(-9) M) with fenoldopam resulted in a synergistic inhibition of Na(+)-K(+)-ATPase activity (66 +/- 2% of control activity), while 20-HETE plus quinpirole had no effect. Furthermore, 20-HETE (10(-9) M) synergized with forskolin (10(-5) M) and with the diacylglycerol analog 1-oleoyl-2-acetoyl-sn-glycerol (OAG; 10(-11) M; 62.0 +/- 5.3 and 69.9 +/- 2.0% of control activity, respectively), indicating a cooperative role of 20-HETE with the D(1)-triggered pathways. In line with these results, no additive effect was observed when OAG and 20-HETE were combined at concentrations which per se produced maximal inhibition (10(-6) M). These results demonstrate that the inhibition of Na(+)-K(+)-ATPase activity by DA in the proximal tubule may be the result of the synergism between 20-HETE and the D(1) signaling pathway.

Pharmacology of signaling induced by dopamine D1-like receptor activation

“…Thus, through these variously interdependent actions, the IP 3 and diacylglycerol arms of the PLC/phosphoinositide signaling system could implement cooperative, complementary, or even synergistic programs in the cell (de Chaffoy et al, 1984). Indeed, the possibility that phospholipid signaling may contribute to the synergistic interactions among dopamine D 1 -like and D 2 -like receptors has been suggested by us and others (Undie, 2002; Kirchheimer et al, 2007), and continues to receive vigorous attention in this laboratory.…”

Potential Dopamine-1 Receptor Stimulation in Hypertension Management

“…Interstitial infusion of fenoldopam, a D1-like specific agonist, caused a proximal tubule-dependent natriuresis in salt-loaded adult rats [65], and coinfusion of an AT2 receptor-specific blocking compound, PD-123319 [66], blocked the effect, suggesting that the AT2 receptor is necessary for the full expression of the effect of D1 receptor activation in promoting sodium excretion. Other natriuretic factors (ANP/ANPA, eicosanoids, nitric oxide, urodilatin) also regulate D1-like receptor function [67][68][69][70]. It is likely that D1-like receptor may play a central role in the natriuretic effects of these factors, as has been shown for prolactin [53].…”

Crosstalk between dopamine receptors and the Na+/K+-ATPase (Review)

“…The synergism of DA and 20-hydroxyeicosatetraenoic acid, a major arachidonic acid metabolite of cytochrome P450, inhibits NKA activity in PCT via the D 1 signaling pathway (82). Urodilatin or DA decreases NKA activity, while urodilatin and DA combined, further decrease NKA activity, demonstrating an additive effect on the sodium pump, suggesting that urodilatin and DA act via a common intracellular pathway to decrease sodium and water tubular reabsorption, contributing to its natriuretic and diuretic effects (83).…”