Abstract-The present study tested the hypothesis that increasing epoxyeicosatrienoic acids by inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure and ameliorate renal damage in salt-sensitive hypertension. Rats were infused with angiotensin and fed a normal-salt diet or an 8% NaCl diet for 14 days. The sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), was given orally to angiotensin-infused animals during the 14-day period. Plasma AUDA metabolite levels were measured, and they averaged 10Ϯ2 ng/mL in normal-salt angiotensin hypertension and 19Ϯ3 ng/mL in high-salt angiotensin hypertension on day 14 in the animals administered the sEH inhibitor. Mean arterial blood pressure averaged 161Ϯ4 mm Hg in normal-salt and 172Ϯ5 mm Hg in the high-salt angiotensin hypertension groups on day 14. EH inhibitor treatment significantly lowered blood pressure to 140Ϯ5 mm Hg in the normal-salt angiotensin hypertension group and to 151Ϯ6 mm Hg in the high-salt angiotensin hypertension group on day 14. The lower arterial blood pressures in the AUDA-treated groups were associated with increased urinary epoxide-to-diol ratios. Urinary microalbumin levels were measured, and ED-1 staining was used to determine renal damage and macrophage infiltration in the groups. Two weeks of AUDA treatment decreased urinary microalbumin excretion in the normal-salt and high-salt angiotensin hypertension groups and macrophage number in the high-salt angiotensin hypertension group. These data demonstrate that sEH inhibition lowers blood pressure and ameliorates renal damage in angiotensin-dependent, salt-sensitive hypertension. Key Words: kidney Ⅲ inflammation Ⅲ endothelium-derived factors Ⅲ albuminuria A lthough treatment of hypertension has significantly advanced in recent decades, a chronic elevation in blood pressure still results in progressive renal damage, as evidenced by the escalating incidence of end-stage renal disease (ESRD). 1,2 The development of hypertension after long-term administration of angiotensin has many of the same renal and vascular changes that are associated with human essential hypertension. 3,4 Likewise, animal models of angiotensindependent hypertension demonstrate a further elevation in blood pressure when fed a high-salt diet or salt sensitivity. [3][4][5] High dietary salt also increases the susceptibility to kidney damage in hypertensive patients and in angiotensindependent hypertensive rats. 3,4 These parallels between patients with essential hypertension and the angiotensin infusion model make this an extremely useful model to evaluate early changes that occur in the kidney that ultimately result in ESRD.Cytochrome P450 epoxygenase metabolites are involved in the long-term regulation of blood pressure and in the response of the kidney to a high-salt diet. 6 -8 Similarly, salt-sensitive hypertension is associated with an inability of the kidney to properly increase epoxygenase levels. 8 -10 Recent studies have provided evidence that increasing epoxygenase levels have renal-and c...
The soluble epoxide hydrolase (sEH) is involved in the metabolism of endogenous chemical mediators that play an important role in blood pressure regulation and inflammation. 1,3-Disubstituted ureas are potent inhibitors of sEH that are active both in vitro and in vivo. However, their poor solubility in either water or lipid reduces their in vivo efficacy and makes them difficult to formulate. To improve these physical properties, the effect of incorporating polar functional groups into one of the alkyl chains was evaluated on their inhibitor potencies, water solubility, octanol/water partition coefficients (log P), and melting points. No loss of inhibition potency was observed when a polar functional group was incorporated at least five atoms ( approximately 7.5 A) from the central urea carbonyl. In addition, the presence of a polar group at least 11 atoms away from the urea carbonyl group for the mouse and human sEHs, respectively, did not alter the inhibitor potency. The resulting compounds have better water solubility and generally lower log P values and melting points than nonfunctionalized liphophilic ureas. These properties will make the compounds more bioavailable and more soluble in either water- or oil-based formulations.
Changes in the lungs due to smoking include inflammation, epithelial damage, and remodeling of the airways. Airway inflammation is likely to play a critical role in the genesis and progression of tobacco smoke-induced airway disease. Soluble epoxide hydrolase (sEH) is involved in the metabolism of endogenous chemical mediators that play an important role in inflammation. Epoxyeicosatrienoic acids (EETs) have demonstrated antiinflammatory properties, and hydrolysis of these epoxides by sEH is known to diminish this activity. To examine whether acute tobacco smokeinduced inflammation could be reduced by a sEH inhibitor, 12-(3-adamantane-1-yl-ureido)-dodecanoic acid n-butyl ester was given by daily s.c. injection to spontaneously hypertensive rats exposed to filtered air or tobacco smoke for a period of 3 days (6 h͞day). Acute exposure to tobacco smoke significantly increased by 3.2-fold (P < 0.05) the number of cells recovered by bronchoalveolar lavage. The sEH inhibitor significantly decreased total bronchoalveolar lavage cell number by 37% in tobacco smoke-exposed rats with significant reductions noted in neutrophils, alveolar macrophages, and lymphocytes. A combination of sEH inhibitor and EETs was more significant in its ability to further reduce tobacco smokeinduced inflammation compared with the sEH inhibitor alone. The sEH inhibitor led to a shift in some plasma epoxides and diols that are consistent with the hypothetical action of these compounds. We conclude that an sEH inhibitor, in the presence or absence of EETs, can attenuate, in part, inflammation associated with acute exposure to tobacco smoke. epoxyeicosatrienoic acids ͉ pulmonary ͉ antiinflammatory
A method for the simultaneous quantification of urinary linoleic and arachidonic acid derived epoxides and diols, as well as the arachidonate omega hydroxylated product has been developed. The method employs negative mode electrospray ionization and HPLC with tandem mass spectroscopy for quantification. Odd chain length saturated epoxy and dihydroxy fatty acids are used as analytical surrogates resulting in linear calibrations ( r 2 у 0.9995). Standard addition analyses showed that matrix effects do not prevent these surrogates from yielding reliable quantitative results. Using 4 ml urine aliquots at a final extract volume of 100 l and injecting 10 l, method detection limits and limits of quantification were р 0.5 and 1.5 nM, respectively. The sensitivity for dihydroxy lipids was from 3-to 10-fold greater than the corresponding epoxy fatty acid. Shot to shot run times of 31 min were achieved. Rodent and human urine analyses indicated the method sensitivity is sufficient for general research applications. In addition, diurnal fluctuations in linoleate and arachidonate derived metabolites were observed in human subjects.
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