Pharmacological modulation of b-adrenoceptors as a new cardioprotective strategy for therapy of myocardial dysfunction induced by ischemia and reperfusion

Abstract Purpose: To evaluate the cardioprotective response of the pharmacological modulation of β-adrenergic receptors (β-AR) in animal model of cardiac ischemia and reperfusion (CIR), in spontaneously hypertensive (SHR) and normotensive (NWR) rats. Methods: CIR was induced by the occlusion of left anterior descendent coronary artery (10 min) and reperfusion (75 min). The SHR was treated with β-AR antagonist atenolol (AT, 10 mg/kg, IV) 5 min before CIR, and NWR were treated with β-AR agonist isoproterenol (ISO, 0.5 mg/kg, IV) 5 min before CIR. Results: The treatment with AT increased the incidence of VA, AVB and LET in SHR, suggesting that spontaneous cardioprotection in hypertensive animals was abolished by blockade of β-AR. In contrast, the treatment with ISO significantly reduced the incidence of ventricular arrhythmia, atrioventricular blockade and lethality in NWR (30%, 20% and 20%, respectively), suggesting that the activation of β-AR stimulate cardioprotection in normotensive animals. Serum CK-MB were higher in SHR/CIR and NWR/CIR compared to respective SHAM group (not altered by treatment with AT or ISO). Conclusion: The pharmacological modulation of β-AR could be a new cardioprotective strategy for the therapy of myocardial dysfunctions induced by CIR related to cardiac surgery and cardiovascular diseases.

摘要

研究目的：本研究旨在评估β肾上腺素能受体（β-adrenergic receptors, β-AR）的药理学调控，在自发性高血压大鼠（spontaneously hypertensive rats, SHR）与正常血压大鼠（normotensive rats, NWR）的心肌缺血再灌注（cardiac ischemia and reperfusion, CIR）动物模型中的心脏保护效应。

研究方法：通过结扎左前降支冠状动脉（10分钟）后再灌注（75分钟）构建CIR模型。于CIR造模前5分钟，对SHR给予β-AR拮抗剂阿替洛尔（atenolol, AT, 10 mg/kg, 静脉注射IV），对NWR给予β-AR激动剂异丙肾上腺素（isoproterenol, ISO, 0.5 mg/kg, 静脉注射IV）。

研究结果：阿替洛尔处理可升高SHR的室性心律失常（ventricular arrhythmia, VA）、房室传导阻滞（atrioventricular blockade, AVB）及致死事件（lethal events, LET）发生率，提示高血压动物的自发性心脏保护作用可被β-AR阻断所抵消。与之相反，异丙肾上腺素处理可显著降低NWR的室性心律失常、房室传导阻滞及致死率（分别为30%、20%和20%），提示β-AR激活可增强正常血压动物的心脏保护作用。与各自的假手术（SHAM）组相比，SHR/CIR与NWR/CIR组的血清肌酸激酶同工酶MB（CK-MB）水平均显著升高，且阿替洛尔或异丙肾上腺素处理未对该指标产生明显影响。

研究结论：β肾上腺素能受体的药理学调控，有望成为针对心脏手术及心血管疾病相关心肌缺血再灌注诱导的心肌功能障碍的新型心脏保护治疗策略。