5,6-EET inhibits ion transport in collecting duct by stimulating endogenous prostaglandin synthesis

Abstract

We examined the mechanism by which the cytochrome P-450 metabolite of arachidonate, 5,6-epoxyeicosatrienoic acid (5,6-EET), modulates electrogenic transport in the rabbit cortical collecting duct (CCD). 5,6-EET depolarized transepithelial voltage (VT) in a concentration-dependent manner with a maximal effect at 1 microM. None of the other EET regioisomers (8,9-, 11,12-, or 14,15-EET; all at 1 microM) affected VT, This action was also stereoselective, with 5(S),6(R)-EET producing a 2.5-fold greater effect on VT than 5(R),6(S)-EET (1 microM each). Like basolateral prostaglandin E2 (PGE2), both luminal and basolateral 5,6-EET increased cytosolic Ca2+ concentration ([Ca2+]i) in the rabbit CCD. Pretreatment with cyclooxygenase inhibitors (10 microM ibuprofen or 5 microM indomethacin) completely blocked both the [Ca2+]i increase and the change in VT. Neither 5,6-epoxy-PGE1 nor 5-hydroxy-PGI1, cyclooxygenase metabolites of 5,6-EET, affected VT. However, when added to primary cultures of rabbit CCDs, 5,6-EET stimulated endogenous PGE2 synthesis. We propose that 5,6-EET stimulates endogenous prostaglandin synthesis, which inhibits electrogenic ion transport in the CCD.

High Potassium Intake Enhances the Inhibitory Effect of 11,12-EET on ENaC

“…7 Application of 5,6-EET has been shown to decrease Na absorption by inhibiting the Na/H exchanger in the rabbit CCD. 19 Because indomethacin abolished the effect of 5,6-EET on Na transport, it was suggested that the effect of 5,6-EET on the Na/H exchanger in the CCD may be mediated by a COX-dependent pathway. We previously demonstrated that 11,12-EET inhibits ENaC in the CCD, 1 suggesting that CYP epoxygenase plays an important role in regulating renal Na transport.…”

Stable 5,6-Epoxyeicosatrienoic Acid Analog Relaxes Coronary Arteries Through Potassium Channel Activation

“…15,33 It is not known whether the COX metabolite of 5,6-EET or activation of COX by 5,6-EET is responsible for 5,6-EET vasoactivity. We developed and tested 2 5,6-EET structural analogs: P-3,9-DPA and P-6,9-DPA.…”

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

“…In this regard, 20-HETE is normally produced by proximal tubules 3,26 and inhibits Na ϩ reabsorption in this nephron segment by inhibiting Na ϩ /K ϩ -ATPase activity. 4,31 EETs have also been reported to inhibit Na ϩ /K ϩ -ATPase activity, 32 inhibit Na ϩ transport in the proximal tubule 33 and rabbit cortical collecting duct, 7 and inhibit vasopressin-stimulated water reabsorption in the collecting duct. 6 20-HETE also plays a critical role in the regulation of Cl Ϫ transport in the TALH 3,5 and inhibits Na ϩ /K ϩ /2Cl -transport by blocking K ϩ channels in the apical membrane of TALH cells, 34 thereby limiting the availability of K ϩ for transport via Na ϩ /K ϩ /2Cl Ϫ transporters.…”

“…1 20-Hydroxyeicosatetraenoic acid (20-HETE) inhibits Na ϩ transport in the proximal tubule and thick ascending limb of the loop of Henle (TALH), [2][3][4][5] and compounds that induce the renal formation of 20-HETE lower blood pressure in Dahl salt-sensitive (DS) rats. 1 Similarly, epoxyeicosatrienoic acids (EETs) inhibit Na ϩ transport in the proximal tubule and collecting duct, 6,7 and increasing the renal levels of EETs with inhibitors of soluble epoxide hydrolase (sEH) reduces blood pressure in spontaneously hypertensive rats (SHRs) 8 and angiotensin II-induced hypertensive rats. 9 However, 20-HETE is also a potent vasoconstrictor, 1 and many investigators have reported that blocking the vascular effects of 20-HETE may contribute to its antihypertensive effect in SHR and other experimental models of hypertension.…”