Schömig A, Richardt G
Department of Cardiology, University of Heidelberg, Germany.
J Cardiovasc Pharmacol. 1990;16 Suppl 5:S105-12.
In myocardial ischemia, sympathetic activity of the heart is closely connected with the progression of cell injury and the incidence of malignant arrhythmias. Adrenergic stimulation of the ischemic myocardium is due to increased local norepinephrine concentrations in the heart, whereas the plasma catecholamine levels are of minor relevance. During the first few minutes of ischemia. efferent sympathetic nerves are activated. Excessive accumulation of norepinephrine, however, is prevented since adenosine, formed in the ischemic myocardium, suppresses exocytotic norepinephrine release, and released norepinephrine is rapidly removed as long as catecholamine reuptake is functional. With progression of ischemia to more than 10 min, the myocardium is no longer protected against excess catecholamine accumulation in the interstitial space because local metabolic release mechanisms become increasingly important. This release, which is independent of central sympathetic activity and extracellular calcium, occurs in two steps: first, norepinephrine escapes from its intracellular storage vesicles and accumulates in the cytoplasma of the neuron; in a second, rate-limiting step, norepinephrine is transported across the plasma membrane into the interstitial space, using the neuronal uptake carrier in reverse of its normal transport direction. Studies using acute and chronic sympathetic denervation and antiadrenergic agents demonstrate that this local metabolic, rather than centrally induced, norepinephrine release is critically involved in the progression of ischemic cell damage and the occurrence of ventricullar fibrillation in early ischemia. As a consequence of local metabolic catecholamine release, extracellular norepinephrine reaches 1,000 times the normal plasma concentration within 20 min of ischemia. Myocardial ischemia results in a temporary supersensitivity to catecholamines of the myocytes. This is due to a twofold increase in alpha1- and a 30% increase of beta-adrenergic receptor number at the cell surface. The sensitization of adenylate cyclase during the first 20 min of total ischemia is followed by a rapid inactivation of the enzyme that also includes the coupling protein Gs. The deleterious combination of extremely high norepinephrine concentrations with an at least temporarily enhanced responsiveness of the tissue to catecholamines is thought to accelerate the propagation of the wavefront of irreversible cell damage in the ischemic myocardium. Moreover, the inhomogenous distribution of catecholamine excess within the heart is considered to promote malignant arrhythmias by unmasking and enhancing electrophysiological disturbances in early ischemia.
在心肌缺血时，心脏的交感神经活动与细胞损伤的进展及恶性心律失常的发生率密切相关。缺血心肌的肾上腺素能刺激是由于心脏局部去甲肾上腺素浓度升高，而血浆儿茶酚胺水平的相关性较小。在缺血的最初几分钟内，传出交感神经被激活。然而，由于缺血心肌中生成的腺苷抑制去甲肾上腺素的胞吐释放，且只要儿茶酚胺再摄取功能正常，释放的去甲肾上腺素就会迅速被清除，因此可防止去甲肾上腺素过度蓄积。随着缺血进展超过10分钟，心肌不再能抵御间质空间中儿茶酚胺的过度蓄积，因为局部代谢释放机制变得越来越重要。这种释放独立于中枢交感神经活动和细胞外钙，分两步发生：首先，去甲肾上腺素从其细胞内储存囊泡中逸出并积聚在神经元的细胞质中；在第二步限速步骤中，去甲肾上腺素利用神经元摄取载体以与其正常转运方向相反的方向穿过质膜进入间质空间。使用急性和慢性交感神经去支配及抗肾上腺素能药物的研究表明，这种局部代谢性而非中枢诱导的去甲肾上腺素释放与缺血性细胞损伤的进展及早期缺血时室颤的发生密切相关。由于局部代谢性儿茶酚胺释放，缺血20分钟内细胞外去甲肾上腺素浓度达到正常血浆浓度的1000倍。心肌缺血导致心肌细胞对儿茶酚胺暂时超敏。这是由于细胞表面α1 -肾上腺素能受体数量增加两倍，β -肾上腺素能受体数量增加30%。在完全缺血的最初20分钟内腺苷酸环化酶致敏，随后该酶迅速失活，这也包括偶联蛋白Gs。极高的去甲肾上腺素浓度与组织对儿茶酚胺至少暂时增强的反应性这一有害组合被认为会加速缺血心肌中不可逆细胞损伤波前的传播。此外，心脏内儿茶酚胺过量的不均匀分布被认为通过揭示和增强早期缺血时的电生理紊乱来促进恶性心律失常。
