Kurz T, Yamada K A, DaTorre S D, Corr P B
Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri 63110.
Eur Heart J. 1991 Dec;12 Suppl F:88-98. doi: 10.1093/eurheartj/12.suppl_f.88.
Several lines of experimental evidence obtained over the last decade indicate that alterations in the alpha 1-adrenergic receptor system may contribute significantly to arrhythmogenesis in the ischaemic heart. Under normal physiological conditions, alpha 1-adrenergic stimulation of myocytes elicits a modest increase in inotropy, a lengthening of repolarization secondary to a decrease in IK through activation of protein kinase C, and a decrease in automaticity in Purkinje cells due to an increase in Na+/K+ ATPase activity. These findings suggest that alpha 1-adrenergic stimulation of the myocardium would elicit an antiarrhythmic effect. However, during both early ischaemia and reperfusion there is an enhanced responsivity to alpha-adrenergic stimulation and a potent antiarrhythmic effect of alpha 1-adrenergic blockade in several species including the conscious dog. This enhanced alpha-adrenergic responsivity may be due to an increase in alpha 1-adrenergic receptors in ischaemic myocardium originating from a site distinct from the intracellular site for trafficking of beta-adrenergic receptors, possibly within or near the sarcolemma. Recently, we developed an isolated adult canine ventricular myocyte preparation which also exhibits a 2- to 3-fold reversible increase in alpha 1-adrenergic receptors in response to severe hypoxia (PO2 = less than 15 mmHg) associated with marked sarcolemmal accumulation of long-chain acylcarnitines (LCA) secondary to hypoxia-induced inhibition of beta-oxidation of fatty acids. The increase in alpha 1-adrenergic receptors is prevented by inhibition of carnitine acyltransferase I which precludes accumulation of LCA. The sarcolemmal accumulation of LCA increases membrane fluidity, suggesting that the alpha 1-adrenergic receptor may be latent within or near the sarcolemma and becomes accessible to a surface ligand only as membrane fluidity is altered. This conclusion is also supported by our findings that hypoxia elicits a marked increase in the coupling of the alpha 1-adrenergic receptor to inositol 1,4,5-trisphosphate (IP3) production in canine myocytes exposed to norepinephrine. IP3 has been shown to mobilize Ca2+ from the sarcoplasmic reticulum, thereby modulating the levels of intracellular Ca2+. Stimulation of hypoxic myocytes with norepinephrine also results in the appearance of delayed after-depolarizations and triggered rhythms, probably in response to an increase in intracellular Ca2+. In conclusion, these findings indicate that the alpha 1-adrenergic system can contribute to arrhythmogenesis in the ischaemic heart and that approaches to reduce the incidence of sudden cardiac death should include blockade of alpha 1-adrenergic receptors.
过去十年间获得的一系列实验证据表明，α1 - 肾上腺素能受体系统的改变可能在缺血性心脏病的心律失常发生过程中起重要作用。在正常生理条件下，α1 - 肾上腺素能对心肌细胞的刺激会引起心肌收缩力适度增加，由于蛋白激酶C的激活导致IK减少，进而使复极化延长，以及由于Na+/K+ ATP酶活性增加，浦肯野细胞的自律性降低。这些发现表明，α1 - 肾上腺素能对心肌的刺激会产生抗心律失常作用。然而，在早期缺血和再灌注期间，包括清醒犬在内的几种物种对α - 肾上腺素能刺激的反应性增强，并且α1 - 肾上腺素能阻断具有强大的抗心律失常作用。这种增强的α - 肾上腺素能反应性可能是由于缺血心肌中α1 - 肾上腺素能受体增加，其来源与β - 肾上腺素能受体转运的细胞内位点不同，可能位于肌膜内或附近。最近，我们开发了一种分离的成年犬心室肌细胞制剂，该制剂在严重缺氧（PO2小于15 mmHg）时也表现出α1 - 肾上腺素能受体可逆性增加2至3倍，这与缺氧诱导的脂肪酸β - 氧化抑制导致长链酰基肉碱（LCA）在肌膜大量积聚有关。通过抑制肉碱酰基转移酶I可防止α1 - 肾上腺素能受体增加，因为该酶可阻止LCA的积聚。LCA在肌膜的积聚增加了膜流动性，这表明α1 - 肾上腺素能受体可能潜伏在肌膜内或附近，只有当膜流动性改变时才会被表面配体识别。我们的研究结果也支持这一结论，即缺氧会使暴露于去甲肾上腺素的犬心肌细胞中α1 - 肾上腺素能受体与肌醇1,4,5 - 三磷酸（IP3）生成的偶联显著增加。IP3已被证明可从肌浆网中释放Ca2+，从而调节细胞内Ca2+水平。用去甲肾上腺素刺激缺氧心肌细胞还会导致延迟后除极和触发节律的出现，这可能是对细胞内Ca2+增加的反应。总之，这些发现表明α1 - 肾上腺素能系统可能在缺血性心脏病的心律失常发生中起作用，并且降低心脏性猝死发生率的方法应包括阻断α1 - 肾上腺素能受体。
