Inhibition of 20-HETE production contributes to the vascular responses to nitric oxide
Inhibition of 20-HETE production contributes to the vascular responses to nitric oxide
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DOI：
10.1161/01.hyp.29.1.320
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发表时间：
1997-01-01
期刊：
影响因子：
8.3
通讯作者：
Roman, RJ
中科院分区：
文献类型：
--
作者：
AlonsoGalicia, M;Drummond, HA;Roman, RJ
一氧化氮（NO）抑制多种含血红素的酶，包括NO合酶和细胞色素P4501 A1和2B 1。本研究检测了NO是否抑制细胞色素P4504 A酶产生20-羟基二十碳四烯酸（20-HETE），以及阻断这种物质的产生是否有助于NO的血管效应。（SNP; 10（-5）、10（-4）和10（-3）mol/L）使与花生四烯酸孵育的肾微粒体产生的20-HETE减少至71 +/-5%、29 +/-4%，和对照的4 +/-2%（n = 5）。使用1-丙胺，3-（2-羟基-2-亚硝基-1-丙基肼基）（n = 3）获得了类似的结果。为了确定20-HETE的抑制是否有助于NO的血管舒张作用，在用苯肾上腺素预收缩的大鼠肾小动脉（n = 5）上，检测了二溴-十二烯基-甲基磺酰亚胺（DDMS）（一种20-HETE形成的选择性抑制剂）对SNP（10（-7）至10（-3）mol/L）反应的影响。SNP以浓度依赖性方式增加血管直径至对照的82 +/-4%。在DDMS（25 μ mol/L）后，SNP（10（-3）mol/L）仅使血管直径增加17 ± 3%。还在硫代丁巴比妥麻醉的Sprague-Dawley大鼠中检查了DDMS对输注NO供体和合成酶抑制剂的平均动脉压（MAP）和肾血流量（RBF）反应的影响。以1、3、5和10 nmol/min输注MAHMA NONOate使MAP降低16 +/- 2、30 +/- 3、40 +/- 5和48 +/- 5 mm Hg，并使肾血管阻力（RVR）降低15 +/-3%、26 +/-2%、30 +/-3%和34 +/- 4%。DDMS（10 mg/kg，n = 7只大鼠）给药后，对1-六胺，6-（2-羟基-1-甲基-2-硝基肼基）N-甲基（MAHMA NONOate）的MAP和RVR反应平均仅为对照组的20%。在其他实验中，给予N-硝基-L-精氨酸（L-NArg）（10 mg/kg IV）后，MAP增加了32 +/- 4%，RBF下降至对照组的56 +/- 5%。DDMS（10 mg/kg，n = 7只大鼠）给药后，MAP仅增加19 +/- 4%，RBF仅下降7 +/- 4%。这些结果表明，NO抑制细胞色素P4504 A酶，抑制20-HETE的产生有助于NO的血管舒张作用。
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 mu mol/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.