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

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 Ca(2+) - 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.

Authors

Barsheshet, Michal,Ertracht, Offir,Boginya, Alexandra,Reuveni, Tal,Atar, Shaul,Szuchman-Sapir, Andrea
Published Date 2021 Dec