The blood pressure–lowering effect of 20-hete blockade in cyp4a14(2/2) mice is associated with natriuresis

Varunkumar Pandey, Victor Garcia, Ankit Gilani, Priyanka Mishra, Frank Fan Zhang, Mahesh P. Paudyal, John R. Falck, Alberto Nasjletti, Wen Hui Wang, Michal Laniado Schwartzman

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Abstract

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(2/2) 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(2/2) hypertensive mice (6124 vs. 6153 mmHg) while having no effect on age-matched normotensive wild-type (WT) male mice. Hypertension in Cyp4a14(2/2) male mice was accompanied by decreased renal perfusion and reduced glomerular filtration rates, which were corrected by treatment with 20-SOLA. Interestingly, Cyp4a14(2/2) 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(2/2) 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(2/2) male mice, presumably, as a result of associated changes in renal hemodynamics and/or direct stimulatory action on tubular sodium reabsorption.

Original languageEnglish (US)
Pages (from-to)412-418
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume363
Issue number3
DOIs
StatePublished - Dec 1 2017

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Natriuresis
Sodium
Blood Pressure
Kidney
Hemodynamics
Hypertension
Loop of Henle
Vasoconstriction
Glomerular Filtration Rate
Drinking Water
Antihypertensive Agents
Androgens
Perfusion
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Water

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

The blood pressure–lowering effect of 20-hete blockade in cyp4a14(2/2) mice is associated with natriuresis. / 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.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 363, No. 3, 01.12.2017, p. 412-418.

Research output: Contribution to journalArticle

Pandey, V, Garcia, V, Gilani, A, Mishra, P, Zhang, FF, Paudyal, MP, Falck, JR, Nasjletti, A, Wang, WH & Schwartzman, ML 2017, 'The blood pressure–lowering effect of 20-hete blockade in cyp4a14(2/2) mice is associated with natriuresis', Journal of Pharmacology and Experimental Therapeutics, vol. 363, no. 3, pp. 412-418. https://doi.org/10.1124/jpet.117.243618
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. / The blood pressure–lowering effect of 20-hete blockade in cyp4a14(2/2) mice is associated with natriuresis. In: Journal of Pharmacology and Experimental Therapeutics. 2017 ; Vol. 363, No. 3. pp. 412-418.
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abstract = "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(2/2) 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(2/2) hypertensive mice (6124 vs. 6153 mmHg) while having no effect on age-matched normotensive wild-type (WT) male mice. Hypertension in Cyp4a14(2/2) male mice was accompanied by decreased renal perfusion and reduced glomerular filtration rates, which were corrected by treatment with 20-SOLA. Interestingly, Cyp4a14(2/2) 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(2/2) 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(2/2) male mice, presumably, as a result of associated changes in renal hemodynamics and/or direct stimulatory action on tubular sodium reabsorption.",
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AU - Mishra, Priyanka

AU - Zhang, Frank Fan

AU - Paudyal, Mahesh P.

AU - Falck, John R.

AU - Nasjletti, Alberto

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AU - Schwartzman, Michal Laniado

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