Department of Pharmacology, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
J Cardiovasc Electrophysiol. 2012 Jun;23(6):650-5. doi: 10.1111/j.1540-8167.2011.02285.x. Epub 2012 Feb 21.
It is generally accepted that at least 2 major mechanisms contribute to sinus node (SN) pacemaking: a membrane voltage (mainly I(f) ) clock and a calcium (Ca) clock (localized submembrane sarcoplasmic reticulum Ca(2+) release during late diastolic depolarization). The aim of this study was to compare the contributions of each mechanism to pacemaker activity in SN and Purkinje fibers (PFs) exhibiting normal or abnormal automaticity.
Conventional microelectrodes were used to record action potentials in isolated spontaneously beating canine SN and free running PF in control and in the presence of 0.1 μM isoproterenol. Ryanodine (0.1-3 μM) and ivabradine (3 μM) were used to inhibit sarcoplasmic reticulum Ca(2+) release or I(f), respectively. To induce automaticity at low membrane potentials, PFs were superfused with BaCl(2). In SN, ivabradine reduced the rate whereas ryanodine had no effect. Isoproterenol significantly accelerated automatic rate, which was decreased by ivabradine and ryanodine. In normally polarized PFs, ryanodine had no effects on the automatic rate in the absence or presence of isoproterenol, whereas ivabradine inhibited both control and isoproterenol-accelerated automaticity. In PF depolarized with BaCl(2), ivabradine decreased BaCl(2) -induced automatic rate while ryanodine had no effect.
In canine SN, I(f) contributes to both basal automaticity and β-adrenergic-induced rate acceleration while the ryanodine-inhibited Ca clock appears more involved in β-adrenergic regulation of pacemaker rate. In PF, normal automaticity depends mainly on I(f). Inhibition of basal potassium conductance results in high automatic rates at depolarized membrane potentials with SN-like responses to inhibition of membrane and Ca clocks.
普遍认为窦房结（SN）起搏至少有 2 种主要机制：膜电压（主要是 I(f)）时钟和钙（Ca）时钟（在舒张晚期去极化期间局部的细胞膜下肌浆网 Ca(2+)释放）。本研究旨在比较在表现出正常或异常自律性的 SN 和浦肯野纤维（PF）中，每种机制对起搏活动的贡献。
使用常规微电极记录在对照和存在 0.1 μM 异丙肾上腺素的情况下，分离的自发搏动犬 SN 和自由运行 PF 的动作电位。使用 Ryanodine（0.1-3 μM）和 Ivabradine（3 μM）分别抑制肌浆网 Ca(2+)释放或 I(f)。为了在低膜电位下诱导自律性，用 BaCl(2) 灌流 PF。在 SN 中，Ivabradine 降低了速率，而 Ryanodine 没有作用。异丙肾上腺素显著加速了自动率，Ivabradine 和 Ryanodine 降低了这种加速。在正常极化的 PF 中，Ryanodine 在不存在或存在异丙肾上腺素的情况下对自动率没有影响，而 Ivabradine 抑制了对照和异丙肾上腺素加速的自律性。在用 BaCl(2) 去极化的 PF 中，Ivabradine 降低了 BaCl(2)诱导的自动率，而 Ryanodine 没有作用。
在犬 SN 中，I(f) 既有助于基础自律性，也有助于 β-肾上腺素能诱导的速率加速，而 Ryanodine 抑制的 Ca 时钟似乎更参与了对起搏速率的 β-肾上腺素能调节。在 PF 中，正常的自律性主要依赖于 I(f)。抑制基础钾电流会导致在去极化膜电位下产生高的自动率，具有类似于 SN 的对膜和 Ca 时钟的抑制反应。
