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. 2021 Dec;1866(12):159031.
doi: 10.1016/j.bbalip.2021.159031. Epub 2021 Aug 21.

Vasodilation and blood pressure-lowering effect mediated by 5,6-EEQ lactone in 5/6 nephrectomy hypertensive rats

Michal Barsheshet  1 , Offir Ertracht  2 , Alexandra Boginya  3 , Tal Reuveni  2 , Shaul Atar  4 , Andrea Szuchman-Sapir  5
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Vasodilation and blood pressure-lowering effect mediated by 5,6-EEQ lactone in 5/6 nephrectomy hypertensive rats

Michal Barsheshet et al. Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Dec.

Abstract

Microvascular dysfunction is a key contributor to vascular hypertension, one of the most common chronic diseases in the world. Microvascular dysfunction leads to the loss of nitric oxide-mediated endothelial dilation and the subsequent compensatory function of endothelium-derived hyperpolarizing (EDH) factors in the regulation of vascular tone. Previously, we showed that lactone metabolite derived from arachidonic acid induces endothelial-dependent vasodilation in isolated human microvessels. Based on structural similarities, we hypothesize that additional lactone metabolites formed from eicosapentaenoic fatty acid (EPA) may bear EDH properties.

Aim: To elucidate the vasodilatory and blood pressure (BP)-reducing characteristics of the 5,6-EEQ (5,6-epoxyeicosatetraenoic acids) lactone (EPA-L) in hypertensive 5/6 nephrectomy (5/6Nx) rats.

Methods: 5/6Nx hypertensive rats intravenously administrated with EPA-L for five days. BP, blood and urine chemistry, and kidney function were detected and analyzed. Vascular dilation was detected using a pressure myograph with or without Ca2+ - activated K+ (KCa) endothelial channel inhibitors. KCNN3 and KCNN4 gene expression (mRNA) detected in mesenteric arteries from 5/6Nx and NT rats.

Results: EPA-L administration to 5/6Nx rats significantly (p < 0.05) reduced BP and heart rate without affecting kidney function. 5/6Nx rat mesenteric arterioles exhibited a lower dilation response to acetylcholine (10-7 mol/l) than normotensive (NT) vessels, while EPA-L administration restored the vessel relaxation response. The EPA-L-driven relaxation of mesenteric arteries was significantly reduced by pretreatment with TRAM-34 and apamin. However, KCa channel expression did not significantly differ between 5/6Nx and NT mesenteric arteries.

Conclusion: EPA-L reduces BP by improving microvessel dilation involving calcium-dependent potassium endothelial channels.

Keywords: 5/6 nephrectomy; Eicosapentaenoic acid; Endothelial-depe hyperpolarizing factors; Hypertension; Microvascular dysfunction.

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