Priori S G, Yamada K A, Corr P B
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Mo 63110.
Circulation. 1991 Jan;83(1):248-59. doi: 10.1161/01.cir.83.1.248.
Although findings from several reports suggest that nonreentrant or focal mechanisms contribute to the genesis of arrhythmias during early ischemia, the contribution of triggered activity arising from early or delayed afterdepolarizations has not been resolved. We have previously demonstrated that beta- but not alpha-adrenergic stimulation induces afterdepolarizations and triggered activity in isolated normoxic myocytes. In the present study, the influence of the extent of cellular derangements as well as increases in [K+]o on alpha- and beta-adrenergic-mediated afterdepolarizations and triggered activity was evaluated. Adult canine myocytes were exposed to one of the following experimental conditions with simultaneous intracellular transmembrane action potential recordings: 1) low PO2 (less than 10 mm Hg, obtained using a specially designed hypoxic chamber) and low (6.8) pH; 2) low PO2, low pH, and high extracellular potassium ([K+]o) (10 mM); or 3) severe metabolic inhibition with cyanide (10(-6) M). Cells from each group were superfused with either the alpha-agonist phenylephrine (10(-5) or 10(-7) M, with 10(-5) M nadolol) or the beta-agonist isoproterenol (10(-6) M). Moderate changes in the action potentials were observed under conditions 1 and 2 (moderate hypoxia), whereas marked but reversible changes were observed with cyanide (severe metabolic inhibition). During moderate hypoxia in normal [K+]o, delayed afterdepolarizations or triggered activity were elicited by both alpha- (12 of 13 cells) and beta-adrenergic (five of five cells) stimulation. Increasing [K+]o during moderate hypoxia completely abolished the afterdepolarizations induced by alpha-adrenergic stimulation and prevented the occurrence of triggered activity. In contrast, the influence of beta-adrenergic stimulation was only attenuated by an increase in [K+]o. Exposure to cyanide completely prevented the induction of afterdepolarizations and triggered activity by both alpha- and beta-adrenergic stimulation. Our findings indicate that moderate hypoxia in normal [K+]o is associated with the development of adrenergic-mediated afterdepolarizations and triggered activity. In contrast, accumulation of [K+]o or severe impairment of cellular metabolism is accompanied by inhibition of adrenergic-mediated afterdepolarizations and triggered activity.
尽管几份报告的研究结果表明，非折返或局灶机制在早期缺血期间心律失常的发生中起作用，但早期或延迟后除极引起的触发活动的作用尚未明确。我们之前已经证明，β-肾上腺素能刺激而非α-肾上腺素能刺激可在分离的正常氧合心肌细胞中诱导后除极和触发活动。在本研究中，评估了细胞紊乱程度以及细胞外钾离子浓度（[K+]o）升高对α-和β-肾上腺素能介导的后除极和触发活动的影响。成年犬心肌细胞在同步记录细胞内跨膜动作电位的情况下，暴露于以下实验条件之一：1）低氧分压（低于10 mmHg，使用专门设计的低氧室获得）和低pH值（6.8）；2）低氧分压、低pH值和高细胞外钾离子浓度（[K+]o）（10 mM）；或3）用氰化物（10(-6) M）进行严重代谢抑制。每组细胞用α-激动剂去氧肾上腺素（10(-5) 或10(-7) M，加10(-5) M纳多洛尔）或β-激动剂异丙肾上腺素（10(-6) M）进行灌流。在条件1和2（中度缺氧）下观察到动作电位有中度变化，而在氰化物处理（严重代谢抑制）时观察到明显但可逆的变化。在正常[K+]o的中度缺氧期间，α-肾上腺素能刺激（13个细胞中的12个）和β-肾上腺素能刺激（5个细胞中的5个）均引发延迟后除极或触发活动。在中度缺氧期间增加[K+]o完全消除了α-肾上腺素能刺激诱导的后除极，并防止了触发活动的发生。相反，β-肾上腺素能刺激的影响仅因[K+]o升高而减弱。暴露于氰化物完全阻止了α-和β-肾上腺素能刺激诱导的后除极和触发活动。我们的研究结果表明，正常[K+]o时的中度缺氧与肾上腺素能介导的后除极和触发活动的发生有关。相反，[K+]o的积累或细胞代谢的严重受损伴随着肾上腺素能介导的后除极和触发活动的抑制。
