Abstract-Previous studies have indicated that the production of 20-hydroxyecisatatraenoic acid (20-HETE) is similar in the liver of C57/B6 mice and rats, but the renal production of 20-HETE is very low in this strain of mice. The present study examined the effects of induction of the renal production of 20-HETE with fenofibrate (FF) on the development of angiotensin II (Ang II)-dependent hypertension in C57BL/6J mice. The mice were divided into 4 groups and treated with vehicle (control), FF (90 mg/kg per day, IP), Ang II (1000 ng/kg per minute, SC), and Ang II plus FF. Mean arterial blood pressure (MAP) averaged 109Ϯ4 and 106Ϯ2 mm Hg in control and FF-treated mice (nϭ7). MAP was significantly increased in the Ang II-treated mice to 144Ϯ4 mm Hg (nϭ7). However, FF treatment prevented the development of Ang II-dependent hypertension, with MAP averaging 115Ϯ5 mm Hg in mice treated with both Ang II plus FF (nϭ7). Renal production of 20-HETE was very low in control (nϭ7) and Ang II-treated (nϭ7) mice and was increased by Ͼ2-fold in FF-treated (nϭ7) and Ang II plus FF-treated (nϭ7) mice. The levels of Cyp4A proteins were markedly increased in the kidneys of mice treated with FF and Ang II plus FF but not in the renal vasculature. These results suggest that upregulation of the production of 20-HETE in renal tubules may contribute to the blood pressure-lowering effects of FF treatment in Ang II-dependent hypertension in C57BL/6J mice. 1 Of these metabolites, 20-hydroxyecisatatraenoic acid (20-HETE) has been reported to inhibit sodium transport and promote natriuresis. 2,3 Studies in Dahl salt-sensitive (Dahl S) rats indicate that production of 20-HETE in the outer medulla is reduced and that this defect contributes to the development of salt-sensitive hypertension in this model. 4,5 Induction of the renal expression of Cyp4a enzymes in the kidney using fibrate compounds has been reported to lower blood pressure in spontaneously hypertensive rats (SHR) and stroke-prone SHR and Dahl S rats. 6,7 The reduction of blood pressure with clofibrate in Dahl S rats was also associated with the normalization of the pressurenatruretic response in this model. 8 In mice, the expression of Cyp4A proteins and renal 20-HETE production is reduced during the development of deoxycorticosterone acetate-salt hypertension. 9 Induction of the renal production of 20-HETE with bezafibrate lowered the blood pressure and improved renal hemodynamics in this model. 10 These studies suggest that a deficiency in the renal production of 20-HETE may promote the development of hypertension. More recently, we have reported that the renal production of 20-HETE is also very low in the kidney of C57BL/6J mice, 11 indicating that they may be a good model to determine the role of CYP metabolites of AA in the regulation of renal function and blood pressure. Thus, the present study examined the effects of induction of the renal production of 20-HETE with FF on the development of Ang II-dependent hypertension in C57BL/6J mice.

This study characterized the time course of changes in cerebral blood flow (CBF) and vascular diameter in a dual-hemorrhage model of subarachnoid hemorrhage (SAH) in rats and examined whether acute blockade of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) with N-(3-chloro-4-morpholin-4-yl)phenyl-N'-hydroxyimido formamide (TS-011) can reverse delayed vasospasm in this model. Rats received an intracisternal injection of blood (0.4 ml) on day 0 and a second injection 2 days later. CBF was sequentially measured using laser-Doppler flowmetry, and the diameters of the cerebral arteries were determined after filling the cerebral vasculature with a casting compound. CBF fell to 67% of control after the first intracisternal injection of blood but returned to a value near control 24 h later. CBF again fell to 63% of control after a second intracisternal injection of blood and remained 30% below control for 5 days. The fall in CBF after the second intracisternal injection of blood was associated with a sustained 30% reduction in the diameters of the middle cerebral, posterior communicating, and basilar arteries. Acute blockade of the synthesis of 20-HETE with TS-011 (0.1 mg/kg i.v.), 5 days after the second SAH, increased the diameters of the cerebral arteries, and CBF returned to control. These results indicate that the rats develop delayed vasospasm after induction of the dual-hemorrhage model of SAH and that blockade of the synthesis of 20-HETE fully reverses cerebral vasospasm in this model. They also implicate 20-HETE in the development and maintenance of delayed cerebral vasospasm.