Pharmacological preconditioning strategy based on organ specific mechanisms

本研究旨在探讨药物预适应抗心肌和肾脏缺血再灌注损伤的作用机制，建立缺血再灌注损伤的药物治疗方法。本研究观察了钙增敏剂MCI-154和异氟醚对慢性仪器犬自主神经活动阻断后心肌收缩功能的影响。在清醒状态和异氟醚麻醉期间，在不改变计算的心肌耗氧量的情况下，MCI-154可增加心肌收缩能力和降低冠脉血管阻力。本文研究了Na/Ca~(2+)交换抑制剂KB-R7943对犬心肌顿抑的血流动力学和心脏保护作用。KB-R7943以剂量依赖的方式改善缺血再灌注后的心肌收缩功能障碍，对冠脉和全身血流动力学无影响。我们检测了Milrino…的保护作用。更多的Ne在临床剂量下使用麻醉猪的心肌顿抑模型。在缺血前或再灌流后给予米力农可预防缺血再灌流引起的心肌顿抑。采用犬冠状动脉微栓塞术模型，观察异丙酚对犬急性缺血心肌收缩功能和氧平衡的影响。异丙酚使急性缺血心肌的收缩能力较正常心肌明显降低，氧失衡不参与其作用机制。我们在离体大鼠心脏上进行研究，以确定右美托咪定是否对缺氧-复氧诱导的左心功能障碍有直接的保护作用，而不是全身血流动力学和体液影响。右美托咪定主要通过α2-肾上腺素能兴奋对缺氧-复氧所致的左心功能不全起到直接保护作用。我们研究了磷酸二酯酶III型抑制剂奥普利酮对大鼠心肌梗死的保护作用。奥普利酮的心脏保护作用可通过激活PI3K-Akt和抑制MPTP发挥作用。我们研究了异氟醚对大鼠肾脏的药理预适应作用，异氟醚在缺血前给予异氟醚对大鼠肾脏缺血/再灌注损伤具有预适应作用。抑制蛋白激酶JNK和ERK可能参与了异氟醚预适应的机制。较少

This study was carried out to investigate the mechanisms of pharmacological preconditioning effects against myocardial and renal ischemia-reperfusion injury and to establish the pharmacological therapeutic method for ischemia-reperfusion injury.We investigated the interaction of MCI-154, a calcium sensitizer, and isoflurane on myocardial contractility in chronically instrumented dogs after pharmacological autonomic nervous system activity blockade. MCI-154 increases myocardial contractility and decreases coronary vascular resistance without changing calculated myocardial oxygen consumption during both the conscious state and isoflurane anesthesia. We investigated the hemodynamic and cardioprotective effects of KB-R7943, a Na+/Ca2+ exchanger inhibitor, on myocardial stunning in dogs. KB-R7943 improves myocardial contractile dysfunction after ischemia-reperfusion in a dose-dependent manner, and has no effect on coronary and systemic hemodynamics. We examined protective effects of milrino … More ne in a clinical dose using the myocardial stunning model of anesthetized swine. Milrinone administered before ischemia or just after reperfusion provides protection against ischemia-reperfusion-induced myocardial stunning. We investigated the effects of propofol on myocardial contractility and oxygen balance in acute ischemic myocardium, using coronary microembolization model in dogs. Propofol causes a greater decrease in the contractility of acute ischemic myocardium as compared with normal myocardium, and oxygen imbalance is not involved in the mechanism of this propofol's action. We investigated to determine whether dexmedetomidine has a direct protective effect against hypoxia-reoxygenation-induced left ventricular dysfunction without systemic hemodynamic and humoral effects in isolated rat hearts. Dexmedetomidine exerts the direct protective effect on the left ventricular dysfunction caused by hypoxia-reoxygenation through mainly alpha 2-adrenergic stimulation. We investigated the cardioprotective effects of olprinone, a phosphodiesterase type III inhibitor, on myocardial infarction in rats. The olprinone-induced cardioprotective effect could be exerted via the activation of PI3K-Akt and the inhibition of mPTP during early reperfusion.We investigated pharmacological preconditioning by isoflurane in the rat kidney, isoflurane has a preconditioning effect against renal ischemia/reperfusion injury when administered before ischemia. Inhibition of the protein kinases, JNK and ERK, might be involved in the mechanisms of isoflurane preconditioning. Less