Levesque P C, Clark C D, Zakarov S I, Rosenshtraukh L V, Hume J R
Department of Physiology, University of Nevada School of Medicine, Reno 89557-0046.
Pflugers Arch. 1993 Jun;424(1):54-62. doi: 10.1007/BF00375102.
Modulation of the ventricular action potential by beta-adrenergic activation of Ca2+, K+ and cyclic adenosine monophosphate (cAMP)-dependent Cl- channels was assessed in enzymatically isolated guinea-pig ventricular myocytes. The effectiveness and relative selectivity of 9-anthracene carboxylic acid (9-AC), as an antagonist of cAMP-dependent Cl- channels was also tested. Membrane currents and action potentials were recorded using the conventional whole-cell variant of the patch-clamp technique or with the amphotericin B perforated-patch technique. The beta-adrenergic agonist isoproterenol either increased or decreased action potential duration depending on whether the dominant effect was on inward Ca2+ currents or on outward K+ or Cl- currents. When Ca2+ and K+ channel modulation was prevented by nisoldipine and low temperature respectively, beta-adrenergic activation of Cl- channels caused a significant reduction in action potential duration and a slight depolarization of the membrane potential. The beta-adrenergic-mediated effects were reversed by the Cl- channel blocker, 9-AC. In the absence of beta-adrenergic stimulation, 9-AC had no detectable effects on action potentials or Ca2+ currents. These results suggest that beta-adrenergic activation of Cl- channels is a potent mechanism for regulation of action potential duration and that 9-AC may be a useful, relatively specific, pharmacological tool for evaluating the physiological role of cAMP-activated Cl- channels in heart. 9-AC also reversed the ability of isoproterenol to antagonize prolongation of action potential duration by the class III antiarrhythmic agent E-4031.
在酶分离的豚鼠心室肌细胞中评估了β-肾上腺素能激活Ca2+、K+和环磷酸腺苷（cAMP）依赖性Cl-通道对心室动作电位的调节作用。还测试了9-蒽甲酸（9-AC）作为cAMP依赖性Cl-通道拮抗剂的有效性和相对选择性。使用膜片钳技术的传统全细胞变体或两性霉素B穿孔膜片技术记录膜电流和动作电位。β-肾上腺素能激动剂异丙肾上腺素增加或减少动作电位持续时间，这取决于主要作用是对内向Ca2+电流还是外向K+或Cl-电流。当分别用尼索地平阻断Ca2+通道调节和用低温阻断K+通道调节时，β-肾上腺素能激活Cl-通道导致动作电位持续时间显著缩短和膜电位轻微去极化。Cl-通道阻滞剂9-AC可逆转β-肾上腺素能介导的效应。在没有β-肾上腺素能刺激的情况下，9-AC对动作电位或Ca2+电流没有可检测到的影响。这些结果表明，β-肾上腺素能激活Cl-通道是调节动作电位持续时间的有效机制，并且9-AC可能是评估cAMP激活的Cl-通道在心脏中的生理作用的有用的、相对特异性的药理学工具。9-AC还逆转了异丙肾上腺素拮抗III类抗心律失常药物E-4031引起的动作电位持续时间延长的能力。
