卡维地洛减轻自身免疫性心肌炎-抗氧化相关的抗炎作用

Carvedilol Ameliorates Autoimmune Myocarditis by Its Antioxidant Property

目的卡维地洛在实验性心脏损伤模型中具有显著的心脏保护作用。本研究探讨是否卡维地洛能减轻自身免疫性心肌炎,并探讨其可能的主要机制。方法 6周龄Lewis大鼠诱导自身免疫性心肌炎,随机分为正常对照、阳性对照、不同剂量的卡维地洛、美多洛尔、普萘洛尔、以及卡维地洛消旋体治疗组。观察其对急性心肌炎症程度,及对炎症心肌内多种炎性细胞因子mRNA表达及蛋白表达、心肌细胞内蛋白氧化产物和细胞膜脂质过氧化产物TBARS含量的影响。结果尽管两种剂量的卡维地洛、美多洛尔和普萘洛尔显示出同等的β受体阻滞作用,只有卡维地洛治疗使心肌炎症得到减轻,心重/体重、炎症分级严重程度明显减轻;卡维地洛消旋体虽无β受体阻滞作用,但心肌炎严重程度也明显减轻;与阳性对照组比较,卡维地洛治疗显著降低蛋白羧基含量和TBARS产物,而美多洛尔和普萘洛尔治疗组则无明显变化;也只有卡维地洛治疗明显降低心肌炎性细胞因子mRNA表达和IL-1β表达。体外实验证实卡维地洛和卡维地洛消旋体保护离体心肌细胞膜的脂质过氧化、并以剂量依赖方式抑制培养的U937细胞LPS刺激后IL-1β释放。结论卡维地洛治疗减轻自身免疫性心肌炎,其心脏保护作用可能与其抗氧化和抑制炎症细胞因子作用有关。

Objective To investigate whether carvedilol protects against experimental autoimmune myocarditis (EAM) attributing to its suppression of inflammatory cytokines and antioxidant properties. Methods EAM was induced in Lewis rats by immunization with porcine cardiac myosin. Various dosages of carvedilol, racemic carvedilol (R-carvedilol), metoprolol, propranolol, or a vehicle were administered to rats with or without EAM for 3 weeks. The blood pressure and heart rate (HR) were determined by the tail-cuff method on days 1, 7, 14 and 21. The histopathology was checked at sacrifice on day 22, and myocardial mRNA expression of inflammatory cytokines and interleukin-1β (IL-1β) protein expression, as well as myocardial protein carbonyl contents, and also myocardial thiobarbituric acid reactive substance (TBARS) products were determined. Results Three β-blockers except R-carvedilol decreased HRs to the same extent. Carvedilol and R-carvedilol, but not metoprolol or propranolol, markedly reduced the severity of myocarditis at the two different dosages. Only carvedilol administration suppressed myocardial mRNA expression of inflammatory cytokines and IL-1β protein expression in myocarditis.In addition, carvedilol and R-carvedilol decreased the myocardial protein carbonyl contents, and also decreased the myocardial TBARS products in rats with EAM. The in vitro study showed that carvedilol and R-carvedilol suppressed IL-1β production in lipopolysaccharide stimulated U937 cells, and that carvedilol and R-carvedilol, but not metoprolol or propranolol, suppressed TBARS products in myocardial membrane challenged to oxidative stress. Conclusion Carvedilol protects against acute EAM in rats, and this superior cardioprotective effect of carvedilol to metoprolol and propranolol may be due to suppression of inflammatory cytokines associated with the antioxidant.