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 g/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 mol/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 -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. Key Words: angiotensin Ⅲ lipids E poxyeicosatrienoic acids (EETs) are important signaling molecules derived from arachidonic acid by the action of cytochrome P450 (CYP) epoxygenases. 1 Endotheliumderived EETs are potent vasodilators involved in the action of the endothelium-derived hyperpolarizing factor (EDHF), 2 lower blood pressure, and increase renal sodium excretion. 1,3 Consequently, it may be possible to attenuate or prevent the development of hypertension by maintaining high intravascular EET concentrations. The arachidonic acid epoxides are metabolized to their di-hydroxyl derivatives (DHETS) by the soluble epoxide hydrolase (sEH), 4 and this hydrophilic modification facilitates their diffusion out of the cells and renal clearance. 5,6 The activity of the sEH is therefore thought to be a major determinant of EET bioavailability. 4 The expression of the sEH is high in a number of organs, including the kidney and the liver, 7 and several publications have suggested that the sEH plays a role in regulation of blood pressure. For example, male sEH Ϫ/Ϫ mice have a lower blood pressure than their control litter mates, 8 and inhibition of sEH using N,NЈ-dicyclohexylurea lowers blood pressure in spontaneously ...

OPRM1 118A>G polymorphism affects both analgesic and respiratory depressive effects of alfentanil. However, while the analgesic effects are already partly decreased in heterozygous carriers, depending on the pain model, the respiratory depressive effects are decreased in homozygous carriers of the variant 118G allele. The therapeutic range of alfentanil was only broadened in homozygous carriers.

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