Otto Anne, Fontaine David, Fontaine Jeanine, Berkenboom Guy
Fundamental Physiology and Pharmacology Department, Université Libre de Bruxelles, Brussels, Belgium.
J Cardiovasc Pharmacol. 2005 Aug;46(2):177-84. doi: 10.1097/01.fjc.0000167010.98177.78.
Nitrate tolerance is associated with an enhanced superoxide anion production and can be attenuated by statins, which interact with the 2 main [eNOS and NAD(P)H oxidase] pathways involved in producing this oxidative stress. Three groups of normocholesterolemic rats were treated: group 1 received rosuvastatin (10 mg/kg/d PO) for 5 weeks and in the last 3 days cotreatment with nitroglycerin (NTG 50 mg/kg/d, subcutaneous injections BID); group 2 received only NTG (50 mg/kg/d BID for the last 3 days); and group 3 served as control. Rings of thoracic aortas from these groups were studied in organ baths. Relaxations to NTG (0.1 nM to 0.1 mM) were determined on phenylephrine-preconstricted rings and O2 production (RLU/10 s/mg dry weight) was assessed by lucigenin and the luminol analogue (L-012) chemiluminescence technique. In group 2 (NTG), the concentration-response curves to NTG were significantly shifted to the right: the pD2 (-log NTG concentration evoking a half-maximal relaxation) was 6.75+/-0.06 (n=7) versus 7.75+/-0.07 (n=7) in group 3 (not exposed to NTG, P<0.05); O2 production was enhanced (10,060+/-1,205, n=7 versus 5,235+/-1,052, n=7; P<0.05). In contrast, in group 1, the rightward shift was attenuated: pD2 value was 7.20+/-0.10 (n=8), P<0.05 versus group 2; O2 production was decreased (5911+/-663; n=9, P<0.05 versus group 2). In addition, before NTG exposure, rosuvastatin treatment decreased p22phox [the essential NAD(P)H oxidase subunit] abundance in the aortic wall and decreased NAD(P)H oxidase activity. In contrast, this treatment did not alter either eNOS abundance or the basal release of endothelium-derived NO. Interestingly, in vivo treatment with apocynin, an NAD(P)H oxidase inhibitor, produced a protection similar to that with rosuvastatin. Long-term rosuvastatin treatment protects against nitrate tolerance in the rat aorta by counteracting NTG-induced increase in O2 production. This protection seems to involve a direct interaction with the NAD(P)H oxidase pathway rather than an up-regulation of the eNOS pathway.
硝酸酯耐受性与超氧阴离子生成增加有关，而他汀类药物可减轻这种情况，他汀类药物与产生这种氧化应激的两条主要途径（内皮型一氧化氮合酶和NAD(P)H氧化酶途径）相互作用。对三组血脂正常的大鼠进行了治疗：第1组接受瑞舒伐他汀（10毫克/千克/天，口服）治疗5周，并在最后3天与硝酸甘油联合治疗（50毫克/千克/天，皮下注射，每日两次）；第2组仅接受硝酸甘油治疗（最后3天，50毫克/千克/天，每日两次）；第3组作为对照。在器官浴槽中研究了这些组大鼠的胸主动脉环。在去氧肾上腺素预收缩的血管环上测定对硝酸甘油（0.1纳摩尔至0.1毫摩尔）的舒张反应，并通过光泽精和鲁米诺类似物（L-012）化学发光技术评估氧气生成（相对光单位/10秒/毫克干重）。在第2组（硝酸甘油组）中，对硝酸甘油的浓度-反应曲线明显右移：pD2（引起半数最大舒张的硝酸甘油浓度的负对数）为6.75±０.06（n = 7），而在第3组（未暴露于硝酸甘油）中为7.75±０.07（n = 7），P<0.05；氧气生成增加（10,060±1,205，n = 7对比5,235±1,052，n = 7；P<0.05）。相比之下，在第1组中，右移减弱：pD2值为7.20±０.10（n = 8），与第2组相比P<0.05；氧气生成减少（5911±663；n = 9，与第2组相比P<0.05）。此外，在暴露于硝酸甘油之前，瑞舒伐他汀治疗可降低主动脉壁中p22phox（NAD(P)H氧化酶的关键亚基）的丰度，并降低NAD(P)H氧化酶活性。相比之下，这种治疗既未改变内皮型一氧化氮合酶的丰度，也未改变内皮源性一氧化氮的基础释放。有趣的是，用NAD(P)H氧化酶抑制剂夹竹桃麻素进行体内治疗产生了与瑞舒伐他汀相似的保护作用。长期瑞舒伐他汀治疗通过抵消硝酸甘油诱导的氧气生成增加来预防大鼠主动脉中的硝酸酯耐受性。这种保护作用似乎涉及与NAD(P)H氧化酶途径的直接相互作用，而不是内皮型一氧化氮合酶途径的上调。
