The Blood Pressure-Lowering Effect of 20-HETE Blockade in Mice Is Associated with Natriuresis.

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The Journal of pharmacology and experimental therapeutics, ISSN: 1521-0103, Vol: 363, Issue: 3, Page: 412-418

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10.1124/jpet.117.243618; 10.3410/f.731185613.793541205
Pandey, Varunkumar; Garcia, Victor; Gilani, Ankit; Mishra, Priyanka; Zhang, Frank Fan; Paudyal, Mahesh P; Falck, John R; Nasjletti, Alberto; Wang, Wen-Hui; Schwartzman, Michal Laniado
Faculty of 1000, Ltd.; American Society for Pharmacology & Experimental Therapeutics (ASPET); Touro Scholar
Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics; Blood Pressure drug effects; Cytochrome P450 Family 4 genetics; Hydroxyeicosatetraenoic Acids antagonists & inhibitors; Natriuresis drug effects; Renal Circulation; Biochemistry; Circulatory and Respiratory Physiology; Medicine and Health Sciences; Pharmacology
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20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) has been linked to pro-hypertensive and anti-hypertensive actions through its ability to promote vasoconstriction and inhibit Na transport in the ascending limb of the loop of Henle, respectively. In this study, we assessed the effects of 20-HETE blockade on blood pressure, renal hemodynamics, and urinary sodium excretion in male mice, which display androgen-driven 20-HETE-dependent hypertension. Administration of 2,5,8,11,14,17-hexaoxanonadecan-19-yl 20-hydroxyicosa-6(Z),15(Z)-dienoate (20-SOLA), a water-soluble 20-HETE antagonist, in the drinking water normalized the blood pressure of male hypertensive mice (±124 vs. ±153 mmHg) while having no effect on age-matched normotensive wild-type (WT) male mice. Hypertension in male mice was accompanied by decreased renal perfusion and reduced glomerular filtration rates, which were corrected by treatment with 20-SOLA. Interestingly, male mice treated with 20-SOLA displayed increased urinary sodium excretion that was paralleled by the reduction of blood pressure suggestive of an antinatriuretic activity of endogenous 20-HETE in the hypertensive mice. This interpretation is in line with the observation that the natriuretic response to acute isotonic saline loading in hypertensive male mice was significantly impaired relative to that in WT mice; this impairment was corrected by 20-SOLA treatment. Hence, endogenous 20-HETE appears to promote sodium conservation in hypertensive male mice, presumably, as a result of associated changes in renal hemodynamics and/or direct stimulatory action on tubular sodium reabsorption.