FUNCTION AND REGULATION OF TRANS-eetS

$763,752P01FY2009HLNIH

New York Medical College, Valhalla NY

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Abstract

The red blood cell (RBC) serves as a reservoir of epoxyeicosatrienpic acids (EETs) that are formed by reactive oxygen species acting on arachidonic acid of phospholipids. A novel frans-EET in the Sn-2 position of RBC phospholipids, a 5,6-trans-EET, was formed in greatest abundance exceeding that of 5,6-c/s-EET and released from RBCs by phospholipase A2. ATP, generated in mM quantities by RBCs, has a biphasic action on RBC EET release, stimulating release at low concentrations and inhibiting EET release at high concentrations. EETs in RBCs are estimated to be 20.2 ng/109 RBCs corresponding to 200 ng in 1 ml of blood. Other formed elements of blood presumably carry EETs/HETEs;we have shown that platelets also contain significant quantities of EETs in their phospholipids. The vasoactivity of 5,6-frans-EET is greater than that of 5,6-c/s-EET when tested on renal interlobar arteries and cremasteric arterioles of the rats. Further, the hydration product of 5,6-trans- EET, the dihydroxy compound - 5,6-erythro-EET - has equal or greater vasoactivity than its parent 5,6-frans-EET. In an experimental model exhibiting a high degree of oxidative stress, the spontaneously hypertensive rat (SHR), the levels of 5,6-frans-EET were double those of normotensive WKY rats. We propose that the RBCs serve as a reservoir for epoxides which on release may act in a vasoregulatory capacity. The 3 AIMS will explore this proposal in detail in several experimental models of oxidative stress. AIM 1: Examine renal synthesis and release of cis- and frans-EETs, the factors that promote their production and their effects on renal blood vessels. Aim 2: Define the response to oxidative stress in terms of changes in production of cis- and trans- EETs/DHTs at sites critical to renal function: for the vasculature, preglomerular microvessels (PGMVs);for the tubules, the thick ascending limb (TAL). Aim 3: Define the Relative Contribution of Trans-EETs/DHTs vs. C/s-EETs/DHTs to the Augmented Renal Vasodilator Response to AA of the SHR vs. Normotensive Rats at Different Levels of Renal Perfusion Pressures.

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