RT Journal Article
SR Electronic
T1 The Blood Pressure–Lowering Effect of 20-HETE Blockade in <em>Cyp4a14(−/−)</em> Mice Is Associated with Natriuresis
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 412
OP 418
DO 10.1124/jpet.117.243618
VO 363
IS 3
A1 Varunkumar Pandey
A1 Victor Garcia
A1 Ankit Gilani
A1 Priyanka Mishra
A1 Frank Fan Zhang
A1 Mahesh P. Paudyal
A1 John R. Falck
A1 Alberto Nasjletti
A1 Wen-Hui Wang
A1 Michal Laniado Schwartzman
YR 2017
UL http://jpet.aspetjournals.org/content/363/3/412.abstract
AB 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 Cyp4a14(−/−) 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 Cyp4a14(−/−) hypertensive mice (±124 vs. ±153 mmHg) while having no effect on age-matched normotensive wild-type (WT) male mice. Hypertension in Cyp4a14(−/−) male mice was accompanied by decreased renal perfusion and reduced glomerular filtration rates, which were corrected by treatment with 20-SOLA. Interestingly, Cyp4a14(−/−) 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 Cyp4a14(−/−) 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 Cyp4a14(−/−) male mice, presumably, as a result of associated changes in renal hemodynamics and/or direct stimulatory action on tubular sodium reabsorption.