摘要
[摘要] 目的探讨p肾上腺素受体(卢受体)信号传导系统,特别是p肾上腺素受体激酶一1(PIARKl)在心力衰竭(心衰)发生发展中的重要作用,以及第三代卢受体阻滞剂卡维地洛在心肌梗死(心梗)后心衰中的保护机制。方法结扎大鼠冠状动脉前降支建立心梗心衰的动物模型,并应用卡维地洛进行干预性治疗。雄性Sp吨Plc—Dawley 大鼠心梗模型建立后,随机分成心梗3周组、4周组和12周组及卡维地洛治疗组。另取假手术组大鼠随机分成假手术3周组、4周组和12周组。卡维地洛治疗组大鼠于心梗模型建立后4周末开始给予卡维地洛10ms／(吨．d)灌胃共8周。观察心梗后不同时相大鼠的左心功能、心室重塑、血浆去甲肾上腺素水平、心肌组织pARKl活性及其 mRNA和蛋白表达、臼受体信号传导的变化以及卡维地洛的干预效果。结果 (1)心梗后大鼠发生心室重塑,充血性心力衰竭形成;(2)心梗后心衰大鼠心肌腺苷酸环化酶基础活性和对异丙肾上腺素激活活性均受到抑制,即p受体信号传导减弱,表现为以p受体脱耦联为特征的p受体减敏;(3)心梗后心衰大鼠交感神经系统(SNS)激活,介导 甽]表达和活性增高,并与心室重塑和心衰进程同步;(4)卡维地洛能够抑制心室重量增加,延缓心室重塑,改善心功能,同时抑制pARKl表达,降低pARKl活性。结论 SNS通过pARKl诱导p受体减敏,可能是心梗后心衰发生、发展的因素;而抑制尽Am;1表达,降低pARKl活性,从而恢复卢受体系统信号传导通路的反应性,是卡维地洛防治,C,衰的机制之一。
Objectives To elucidate the molecular changes of the β-adrenoceptor （β-AR） system in a rat model of heart failure after myocardial ilffarction, to study the role of β-adrenergic receptor kinase-1 （βARK1） in the progression of congestive heart failure, and to explore the mechanisms of β-adrenergic receptor blocker carvedilol in therapy of heart failure. Methods Male Sprague-Dawley rats underwent left deseending coronary artery ligation to pxxxtuce myocardial infaretion（ MI）, or thoracotomy only（sham operation）. The MI rats were randomly divided into 3-week group, 4-week group, 12-week group and carvedilol-treated group after operation. Simultaneously, the sham-operated rats were randomly divided into 3-week group, 4-week group and 12- week group. Four weeks after operation, the rats in carvedilol-treated group were given carvedilol by gastric gavage for 8 weeks. The alteration of left ventricular function and remodeling, noradrenaline release in circulation, myocardial β-ARK1 levels and activity, β-AR signaling characteristics were observed. The effect of carvedilol on left ventricular function and remodeling, as well as the possible implication of the β-ARK1 during heart failure due to MI were investigated. Results （ 1 ） Physiological parameters of cardiac dysfunction in MI rats indicated cardiac remodeling and failing heart. （2） MI rats accompanied by heart failure showed reduced myocardial β-AR signaling, exhibiting functional uncoupling of myocardial β adrenergic receptors suggestive of β-AR desensitization. （3） MI rats accompanied by heart failure presented enhanced sympathetic nervous system activity, resulting in elevated βARK1 expression and activity, which was consistent with cardiac remodeling and heart failure. （4） Heart failure due to MI can be attenuated by carvedilol via inhibiting βARKI expression and βARK1 activity. Conclusions Enhanced sympathetic nervous system activity was present in heart failure subsequent to MI and was the trigger for elevated βARK1 expression and βARK1 activity, resulting in functional uncoupling of myocardial β adrenergic receptors, β-AR desensitization, and reduced cardiac function. This suggests that βARK1-induced β-AR desensitization plays a critical role in the development of heart failure. βARK1 appears to be a novel target for carvedilol in the treatment of heart failure.
出处
《中华老年多器官疾病杂志》
2005年第4期287-292,共6页
Chinese Journal of Multiple Organ Diseases in the Elderly
