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目的探讨异丙肾上腺素(ISO)长期刺激其受体对心肌细胞凋亡的影响。方法实验用雄性小鼠30只,分为3组,盐水对照组、ISO刺激组和ISO+SB203580干预组,分别通过埋植渗透给药泵持续给予盐水、ISO[30 mg/(kg.d)]或ISO+p38抑制剂SB203580[10 mg/(kg.d)],共7 d,随后取血清及心肌组织测定指标。结果慢性ISO刺激引起明显的心肌肥厚和细胞凋亡,增加血清和心肌中炎症因子白介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)的生成(P<0.01),增加诱生型一氧化氮合酶(i NOS)的表达(63%)、一氧化氮(NO)及过氧化亚硝酸盐的生成(P<0.01)。SB203580干预后,p38激酶活性抑制,血浆和心肌中IL-6和TNF-α等炎症因子生成减少[干预组与ISO组比较,IL-6:(22.26±6.38)ng/Lvs(51.32±9.20)ng/L,TNF-α:(11.75±1.09)ng/Lvs(8.64±1.01)ng/L,P<0.01],i NOS的表达及其介导的NO生成和过氧化亚硝酸盐损伤减少[干预组与ISO组比较,NO:(38.60±6.60)μmol/g蛋白vs(58.80±13.28)μmol/g蛋白;硝基酪氨酸:(2.86±0.43)μg/g蛋白vs(4.20±0.47)μg/g蛋白,P<0.01],超氧阴离子生成也减少。结论本研究表明,慢性异丙肾上腺素刺激可以引起心肌细胞凋亡,这种致凋亡损伤可能是通过激活p38激酶,促进炎症因子生成,激活i NOS,增加自由基生成和损伤造成的。
Objective To investigate the effects of isoproterenol (ISO) on cardiomyocyte apoptosis induced by its receptor for a long time. Methods Thirty male mice were randomly divided into three groups: saline control group, ISO stimulation group and ISO + SB203580 intervention group. Saline was infused continuously through osmotic drug delivery pump, ISO [30 mg / (kg · d) ] Or ISO + p38 inhibitor SB203580 [10 mg / (kg · d)] for 7 days, followed by determination of serum and myocardial tissue. Results Chronic ISO stimulation induced significant cardiac hypertrophy and apoptosis, increased the production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in serum and myocardium (P <0.01) Nitric oxide synthase (iNOS) expression (63%), nitric oxide (NO) and peroxynitrite (P <0.01). After intervention with SB203580, the p38 kinase activity was inhibited and the production of inflammatory cytokines such as IL-6 and TNF-α in plasma and myocardium were decreased [IL-6: (22.26 ± 6.38) ng / L vs 51.32 ± 9.20 (P <0.01). The expression of iNOS and the NO production and nitrite damage induced by TNF-α were significantly lower than those in control group (P <0.01) Compared with the ISO group, NO (38.60 ± 6.60) μmol / g protein vs (58.80 ± 13.28) μmol / g protein and nitrotyrosine: 2.86 ± 0.43 μg / g protein vs 4.20 ± 0.47, μg / g protein, P <0.01] and superoxide anion production also decreased. Conclusion This study shows that chronic isoproterenol stimulation can induce cardiomyocyte apoptosis, which may be caused by the activation of p38 kinase, the promotion of inflammatory cytokines, activation of i NOS, increase of free radical generation and injury.