Szekeres László
Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical Center, University of Szeged, Szeged, Hungary.
Exp Clin Cardiol. 2004 Spring;9(1):7-12.
In 1983, a delayed and prolonged cardioprotection induced by drugs was described. This pharmacologically induced adaptation to stress represents a new trend in cardioprotection as opposed to the classical drug treatment that was based on the presence of drug-receptor binding. Such a long-lasting, delayed adaptation can be induced by non-injurious pharmacological stimuli (eg, prostacyclin and its stable analogues, catecholamines and other substances) and manifests as a marked protection against the severe consequences of ischemia; attenuation of early morphological changes (limitation in infarct size) and reduction in ventricular arrhythmias as results of coronary artery occlusion and reperfusion or ouabain toxication. The protection is time- and dose-dependent; the maximum effects occur 24 h and 48 h after drug treatment. These effects can be prolonged for a longer period by the periodic administration of maintenance doses. Concerning the mechanism of this marked delayed protection, the findings show that these adaptive stresses stimulate the adenylate cyclase/cyclic AMP (cAMP) system and result in elevation in cardiac cAMP level. This triggers the induction of Na(+)/K(+)-ATPase and activates phosphodiesterase (PDE) isoforms, most likely PDE1 and PDE4. The increased amount of PDE isoforms and activated Na(+)/K(+)-ATPase moderates ischemic myocardial potassium loss, and reduces sodium and calcium accumulation during myocardial ischemia. This also attenuates ouabain toxicity. Induction of PDE isoforms may lead to a reduction in the accumulation of excess cAMP and contribute to a lessened response to beta-adrenergic stimuli. The antiarrhythmic effects can be explained by electrophysiological changes, such as prolongations of the effective refractory period and the action potential duration during ischemia and reperfusion. The advantages of pharmacologically induced adaptation to stress in preventive therapy are that an exact dosage can be applied, the risk of the harmful effects is minimal, the protection can be prolonged, and it can be induced under pathological conditions (eg, atherosclerosis, hypercholesterolemia). Pharmacologically induced long-term protection may represent a new approach in the therapy of cardiovascular diseases.
1983年，有人描述了药物诱导的延迟和延长的心脏保护作用。这种由药理学诱导的对压力的适应性代表了心脏保护领域的一个新趋势，与基于药物-受体结合的传统药物治疗相反。这种持久的、延迟的适应性可由非损伤性药理学刺激（如前列环素及其稳定类似物、儿茶酚胺和其他物质）诱导，并表现为对缺血严重后果的显著保护作用；减轻早期形态学变化（梗死面积受限）以及减少冠状动脉闭塞和再灌注或哇巴因中毒导致的室性心律失常。这种保护作用具有时间和剂量依赖性；在药物治疗后24小时和48小时出现最大效应。通过定期给予维持剂量，这些效应可以延长更长时间。关于这种显著延迟保护作用的机制，研究结果表明，这些适应性应激刺激腺苷酸环化酶/环磷酸腺苷（cAMP）系统，导致心脏cAMP水平升高。这触发了Na(+)/K(+)-ATP酶的诱导，并激活磷酸二酯酶（PDE）亚型，最可能是PDE1和PDE4。PDE亚型数量的增加和激活的Na(+)/K(+)-ATP酶可减轻缺血心肌的钾流失，并减少心肌缺血期间的钠和钙蓄积。这也减轻了哇巴因毒性。PDE亚型的诱导可能导致过量cAMP蓄积减少，并有助于减轻对β-肾上腺素能刺激的反应。抗心律失常作用可以通过电生理变化来解释，如缺血和再灌注期间有效不应期和动作电位持续时间的延长。药理学诱导的对压力的适应性在预防性治疗中的优点是可以应用精确的剂量，有害效应的风险最小，保护作用可以延长，并且可以在病理条件下（如动脉粥样硬化、高胆固醇血症）诱导产生。药理学诱导的长期保护作用可能代表了心血管疾病治疗的一种新方法。
