Hoagland Kimberly M, Flasch Averia K, Roman Richard J
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Hypertension. 2003 Oct;42(4):669-73. doi: 10.1161/01.HYP.0000084634.97353.1A. Epub 2003 Jul 21.
This study examined whether chronic blockade of epoxyeicosatrienoic acids (EETs) and/or 20-hydroxyeicosatetraenoic acid (20-HETE) formation promotes development of salt-sensitive hypertension. Changes in blood pressure, renal cytochrome P450 metabolism of arachidonic acid, and 20-HETE excretion in response to a high salt diet were measured in rats chronically treated with 1-aminobenzotriazole (ABT, 50 mg/kg per day) to block EETs and 20-HETE formation or N-hydroxy-N'-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) that selectively reduces 20-HETE formation. ABT reduced blood pressure in rats fed a low salt (0.4% NaCl) diet, but blood pressure rose by 20 mm Hg after these rats were switched to a high salt (8% NaCl) diet for 10 days. HET0016 had no effect on blood pressure in rats fed a low salt diet; however, blood pressure rose by 18 mm Hg after the rats were fed a high salt diet. 20-HETE formation in kidney homogenates rose by 30% and epoxygenase activity doubled when rats were fed a high salt diet. Chronic treatment with ABT and HET0016 inhibited the renal formation of 20-HETE by approximately 90%. Renal epoxygenase activity decreased by 76% in ABT-treated rats and was not significantly altered in rats treated with HET0016. 20-HETE excretion rose from 470+/-21 to 570+/-41 ng/d when the rats were switched from the low to the high salt diet. 20-HETE excretion fell by 68% and 85% in rats that were chronically treated with ABT and HET0016. These results suggest that chronic blockade of the formation of 20-HETE promotes the development of salt-sensitive hypertension in rats.
本研究考察了环氧二十碳三烯酸（EETs）和/或20-羟基二十碳四烯酸（20-HETE）生成的长期阻断是否会促进盐敏感性高血压的发展。在长期用1-氨基苯并三唑（ABT，每天50mg/kg）处理以阻断EETs和20-HETE生成的大鼠，或用选择性减少20-HETE生成的N-羟基-N'-（4-丁基-2-甲基苯基）甲脒（HET0016，每天10mg/kg）处理的大鼠中，测量了血压变化、肾脏中花生四烯酸的细胞色素P450代谢以及对高盐饮食的反应中20-HETE的排泄情况。ABT降低了喂食低盐（0.4%NaCl）饮食大鼠的血压，但在这些大鼠改为高盐（8%NaCl）饮食10天后，血压升高了20mmHg。HET0016对喂食低盐饮食大鼠的血压没有影响；然而，在大鼠喂食高盐饮食后，血压升高了18mmHg。当大鼠喂食高盐饮食时，肾脏匀浆中20-HETE的生成增加了约30%，环氧酶活性增加了一倍。用ABT和HET0016长期处理可使肾脏中20-HETE的生成抑制约90%。在ABT处理的大鼠中，肾脏环氧酶活性降低了76%，而在HET0016处理的大鼠中没有显著改变。当大鼠从低盐饮食改为高盐饮食时，20-HETE排泄量从470±21增加到570±41ng/d。在长期用ABT和HET0016处理的大鼠中，20-HETE排泄量分别下降了68%和85%。这些结果表明，长期阻断20-HETE的生成会促进大鼠盐敏感性高血压的发展。
