抑制20-羟基二十碳四烯酸（20-HETE）的生成有助于血管对一氧化氮的反应。
Inhibition of 20-HETE production contributes to the vascular responses to nitric oxide.
作者信息
Alonso-Galicia M, Drummond H A, Reddy K K, Falck J R, Roman R J
机构信息
Department of Physiology, Medical College of Wisconsin, Milwaukee 53226-0509, USA.
出版信息
Hypertension. 1997 Jan;29(1 Pt 2):320-5. doi: 10.1161/01.hyp.29.1.320.
Nitric oxide (NO) inhibits a variety of heme-containing enzymes, including NO synthase and cytochrome P4501A1 and 2B1. The present study examined whether NO inhibits the production of 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P4504A enzymes and whether blockade of the production of this substance contributes to the vascular effects of NO. Sodium nitroprusside (SNP; 10(-5), 10(-4), and 10(-3) mol/L) reduced the production of 20-HETE by renal microsomes incubated with arachidonic acid to 71 +/- 5%, 29 +/- 4%, and 4 +/- 2% of control, respectively (n = 5). Similar results were obtained with the use of 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) (n = 3). To determine whether inhibition of 20-HETE contributes to the vasodilatory effects of NO, the effects of dibromo-dodecenyl-methylsulfimide (DDMS), a selective inhibitor of the formation of 20-HETE, on the response to SNP (10(-7) to 10(-3) mol/L) were examined in rat renal arterioles preconstricted with phenylephrine (n = 5). SNP increased vascular diameter in a concentration-dependent manner to 82 +/- 4% of control. After DDMS (25 mumol/L), SNP (10(-3) mol/L) increased vascular diameter by only 17 +/- 3%. The effects of DDMS on the mean arterial pressure (MAP) and renal blood flow (RBF) responses to infusion of an NO donor and a synthase inhibitor were also examined in thiobutabarbital-anesthetized, Sprague-Dawley rats. Infusion of MAHMA NONOate at 1, 3, 5, and 10 nmol/min reduced MAP by 16 +/- 2, 30 +/- 3, 40 +/- 5, and 48 +/- 5 mm Hg and lowered renal vascular resistance (RVR) by 15 +/- 3%, 26 +/- 2%, 30 +/- 3%, and 34 +/- 4% of control. After DDMS (10 mg/kg, n = 7 rats), the MAP and RVR responses to 1-hexamine, 6-(2-hydroxy-1-methyl-2-nitrohydrazino)N-methyl (MAHMA NONOate) averaged only 20% of those seen during control. In other experiments, MAP increased by 32 +/- 4% and RBF fell to 56 +/- 5% of control after administration of N-nitro-L-arginine (L-NArg) (10 mg/kg IV). After DDMS (10 mg/kg, n = 7 rats), MAP increased by only 19 +/- 4% and RBF fell by only 7 +/- 4% after L-NArg. These results indicate that NO inhibits cytochrome P4504A enzymes and that inhibition of the production of 20-HETE contributes to the vasodilatory effects of NO.
一氧化氮（NO）可抑制多种含血红素的酶，包括一氧化氮合酶以及细胞色素P4501A1和2B1。本研究探讨了NO是否抑制细胞色素P4504A酶生成20-羟基二十碳四烯酸（20-HETE），以及阻断该物质的生成是否对NO的血管效应有影响。硝普钠（SNP；10⁻⁵、10⁻⁴和10⁻³mol/L）分别将与花生四烯酸一起孵育的肾微粒体中20-HETE的生成量降至对照的71±5%、29±4%和4±2%（n = 5）。使用1-丙胺，3-（2-羟基-2-亚硝基-1-丙基肼基）（n = 3）也得到了类似结果。为了确定抑制20-HETE是否对NO的血管舒张作用有影响，在预先用去氧肾上腺素收缩的大鼠肾小动脉中，研究了20-HETE形成的选择性抑制剂二溴-十二碳烯基-甲基磺酰亚胺（DDMS）对SNP（10⁻⁷至10⁻³mol/L）反应的影响（n = 5）。SNP以浓度依赖方式使血管直径增加至对照的82±4%。在给予DDMS（25μmol/L）后，SNP（10⁻³mol/L）仅使血管直径增加17±3%。还在硫喷妥巴比妥麻醉的Sprague-Dawley大鼠中研究了DDMS对平均动脉压（MAP）和肾血流量（RBF）对输注NO供体和合成酶抑制剂反应的影响。以1、3、5和10 nmol/min的速度输注MAHMA NONOate可使MAP分别降低16±2、30±3、40±5和48±5 mmHg，并使肾血管阻力（RVR）降低至对照的15±3%、26±2%、30±3%和34±4%。在给予DDMS（10 mg/kg，n = 7只大鼠）后，对1-己胺，6-（2-羟基-1-甲基-2-硝基肼基）N-甲基（MAHMA NONOate）的MAP和RVR反应平均仅为对照期间的20%。在其他实验中，静脉注射N-硝基-L-精氨酸（L-NArg）（10 mg/kg）后，MAP升高32±4%，RBF降至对照的56±5%。给予DDMS（10 mg/kg，n = 7只大鼠）后，L-NArg给药后MAP仅升高19±4%，RBF仅降低7±4%。这些结果表明，NO抑制细胞色素P4504A酶，并且抑制20-HETE的生成有助于NO的血管舒张作用。
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