Soluble epoxide hydrolase is a main effector of angiotensin II-induced hypertension

Oliver Jung, Ralf P. Brandes, In Hae Kim, Frank Schweda, Ronald Schmidt, Bruce D. Hammock, Rudi Busse, Ingrid Fleming

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

The soluble epoxide hydrolase (sEH) metabolizes vasodilatory epoxyeicosatrienoic acids (EETs) to their di-hydroxy derivatives. We hypothesized that the metabolism of EETs by the sEH contributes to angiotensin II-induced hypertension and tested the effects of a water-soluble sEH inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) on blood pressure. AUDA (130 μg/mL in drinking water) did not affect blood pressure in normotensive animals but markedly lowered it in mice with angiotensin II-induced hypertension (1 mg/kg per day). The effect of AUDA was accompanied by an increase in urinary salt and water excretion. Intravenous application of AUDA (8 mg/kg) acutely lowered blood pressure and heart rate in animals with angiotensin II-induced hypertension but failed to affect blood pressure in animals with phenylephrine-induced hypertension (29 mg/kg per day). AUDA (0.1 μmol/L) selectively lowered vascular resistance in an isolated perfused kidney preparation from angiotensin II-pretreated mice but not from control mice. In the perfused hind limb and in isolated carotid arteries from angiotensin II-treated mice, AUDA was without effect. The ω-hydroxylase inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide, which attenuates formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid, decreased tone in carotid arteries from angiotensin II-treated but not from control mice. These data demonstrate that the decrease in blood pressure observed after sEH inhibition in angiotensin II-induced hypertension can be attributed to an initial reduction in heart rate followed by pressure diuresis resulting from increased perfusion of the kidney. Direct vasodilatation of resistance arteries in skeletal muscles does not appear to contribute to the antihypertensive effects of sEH inhibition in mice.

Original languageEnglish (US)
Pages (from-to)759-765
Number of pages7
JournalHypertension
Volume45
Issue number4 SUPPL.
DOIs
StatePublished - Apr 2005

Keywords

  • Angiotensin
  • Lipids

ASJC Scopus subject areas

  • Internal Medicine

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    Jung, O., Brandes, R. P., Kim, I. H., Schweda, F., Schmidt, R., Hammock, B. D., Busse, R., & Fleming, I. (2005). Soluble epoxide hydrolase is a main effector of angiotensin II-induced hypertension. Hypertension, 45(4 SUPPL.), 759-765. https://doi.org/10.1161/01.HYP.0000153792.29478.1d