Fontaine David, Otto Anne, Fontaine Jeanine, Berkenboom Guy
Laboratory of Physiology and Pharmacology, Institute of Pharmacy, ULB, Brussels, Belgium.
Cardiovasc Drugs Ther. 2003 Mar;17(2):123-8. doi: 10.1023/a:1025383601304.
Recent studies have shown that statins seem to upregulate the endothelial NO synthase pathway (eNOS) and may, therefore, enhance NO availability, a direct scavenger of O2- and an inhibitor of oxidative enzymes.
To assess whether the oxidative stress produced by an in vivo exposure to nitroglycerin (NTG) is attenuated by statins, 4 groups of normocholesterolemic rats were treated; group 1 received pravastatin (20 mg/kg/d p.o) and group 2 atorvastatin (10 mg/kg/d) both for 5 weeks and the last 3 days, a cotreatment with the statin plus NTG (50 mg/kg/d, s.c. injections b.i.d.); group 3 (NTG) received only NTG (50 mg/kg/d, b.i.d. for 3 days) and group 4 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 (counts/10 s/mg) was assessed by lucigenin chemiluminescence technique.
In vivo NTG exposure induced a rightward shift of the concentration-response curves to NTG: the pD2 (-log NTG concentration evoking a half maximal relaxation) was 5.8 +/- 0.3 (n=7) vs. 7.2 +/- 0.2 in the control group (not exposed to NTG, n=7) and O2- production was enhanced (1259 +/- 71 vs. 787 +/- 76, (n=5) P<.05). In contrast, groups 1 (n=7) and 2 (n=7) behaved as the control group (pD2 values were 7.4 +/- 0.1 (n=7) and 6.9 +/- 0.1 (n=7); O2- production was 721 +/- 109 and 647 +/- 121). The protective effect on nitrate tolerance disappeared when L-NAME (an eNOS inhibitor, 100 mg/kg/d) was co-administered with NTG in groups 1 and 2. Incubation of aortic rings with NAD(P)H (100 microM) also impaired the protective effect of both statins. Moreover, before NTG exposure, aortic cGMP content, reflecting EDNO availability, was significantly enhanced in group 1 (P<.05 vs. control).
Long-term statin treatment protects against nitrate tolerance by counteracting NTG-induced increase in O2- production. Both eNOS pathway and NAD(P)H oxidases seem to be involved in this protective mechanism.
近期研究表明，他汀类药物似乎可上调内皮型一氧化氮合酶途径（eNOS），因此可能会增加一氧化氮（NO）的生成，NO是O2-的直接清除剂及氧化酶的抑制剂。
为评估他汀类药物是否能减轻体内暴露于硝酸甘油（NTG）所产生的氧化应激，对4组血脂正常的大鼠进行了治疗；第1组大鼠口服普伐他汀（20mg/kg/d），第2组大鼠口服阿托伐他汀（10mg/kg/d），均持续5周，在最后3天，他汀类药物与NTG联合治疗（50mg/kg/d，皮下注射，每日2次）；第3组（NTG组）仅接受NTG治疗（50mg/kg/d，每日2次，共3天），第4组作为对照组。对这些组的胸主动脉环在器官浴槽中进行研究。在去氧肾上腺素预收缩的血管环上测定对NTG（0.1nM至0.1mM）的舒张反应，并通过光泽精化学发光技术评估O2-生成量（计数/10秒/毫克）。
体内暴露于NTG导致对NTG的浓度-反应曲线右移：pD2（引起半数最大舒张的-log NTG浓度）在对照组（未暴露于NTG，n = 7）中为7.2±0.2，而在NTG暴露组中为5.8±0.3（n = 7），并且O2-生成增加（1259±71对787±76，（n = 5）P<0.05）。相比之下，第1组（n = 7）和第2组（n = 7）的表现与对照组相同（pD2值分别为7.4±0.1（n = 7）和6.9±0.1（n = 7）；O2-生成量分别为721±109和647±121）。当在第1组和第2组中L-NAME（一种eNOS抑制剂，100mg/kg/d）与NTG联合给药时，对硝酸酯耐受性的保护作用消失。用NAD(P)H（100μM）孵育主动脉环也损害了两种他汀类药物的保护作用。此外，在暴露于NTG之前，反映内皮源性NO可用性的主动脉环cGMP含量在第1组中显著增加（与对照组相比，P<0.05）。
长期他汀类药物治疗可通过抵消NTG诱导的O2-生成增加来预防硝酸酯耐受性。eNOS途径和NAD(P)H氧化酶似乎都参与了这一保护机制。
