Wang Y G, Lipsius S L
Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Ill., USA.
Circ Res. 1996 Jul;79(1):109-14. doi: 10.1161/01.res.79.1.109.
Vagal nerve-induced inhibition of the heartbeat is followed by a postvagal increase in heart rate above control levels, postvagal tachycardia. In the present study, we used a perforated-patch/whole-cell recording method to determine the role of L-type Ca2+ current (ICa,L) and the hyperpolarization-activated inward current (I(f)) in the positive chronotropic response elicited by withdrawal of acetylcholine (ACh). Experiments were performed on sinoatrial node (SAN) and latent atrial pacemaker (LAP) cells isolated from cat right atrium. Withdrawal of a 2-minute exposure to 1 mumol/L ACh elicited a rebound stimulation of ICa,L in both SAN (33 +/- 4%) and LAP (50 +/- 6%) cells above control. Similarly, withdrawal of ACh (1 mumol/L) elicited a rebound stimulation of I(f) in both SAN (21 +/- 4%) and LAP (20 +/- 6%) cells. During the rebound stimulation of ICa,L, peak amplitude was increased throughout the voltage range, and the voltage dependence of activation was shifted to more negative voltages. Action potential recordings from both SAN and LAP cells showed that following ACh-induced inhibition, withdrawal of ACh elicited a concomitant rebound increase in action potential amplitude ( + 21 +/- 2% and + 21 +/- 3%, respectively) and decrease in pacemaker cycle length (30 +/- 5% and 44 +/- 5%, respectively) compared with control. H-89 (2 mumol/L), an inhibitor of cAMP-dependent protein kinase A, abolished the rebound increase of ICa,L, I(f), action potential amplitude, and decrease in pacemaker cycle length elicited by withdrawal of ACh. In the presence of 2 mmol/L cesium, a blocker of I(f), the rebound decrease in pacemaker cycle length elicited by withdrawal of ACh was unchanged. We conclude that in SAN and LAP cells, withdrawal of ACh elicits a positive chronotropic response primarily through a cAMP-mediated rebound stimulation of ICa,L. These findings are the first demonstration of an intrinsic cellular mechanism that may contribute directly to the nonadrenergic component of postvagal tachycardia.
迷走神经诱导的心跳抑制之后会出现迷走神经节后心率高于对照水平的增加，即迷走神经节后心动过速。在本研究中，我们使用穿孔膜片/全细胞记录方法来确定L型钙电流（ICa,L）和超极化激活内向电流（I(f)）在乙酰胆碱（ACh）撤除所引发的正性变时反应中的作用。实验在从猫右心房分离出的窦房结（SAN）和潜在心房起搏细胞（LAP）上进行。撤除2分钟1 μmol/L ACh的暴露后，SAN细胞（33±4%）和LAP细胞（50±6%）中的ICa,L均出现高于对照的反弹刺激。同样，撤除ACh（1 μmol/L）会引发SAN细胞（21±4%）和LAP细胞（20±6%）中I(f)的反弹刺激。在ICa,L的反弹刺激期间，整个电压范围内峰值幅度均增加，激活的电压依赖性向更负的电压偏移。来自SAN和LAP细胞的动作电位记录显示，与对照相比，在ACh诱导的抑制之后，撤除ACh会伴随动作电位幅度的反弹增加（分别为+21±2%和+21±3%）以及起搏周期长度的缩短（分别为30±5%和44±5%）。cAMP依赖性蛋白激酶A的抑制剂H-89（2 μmol/L）消除了撤除ACh所引发的ICa,L、I(f)、动作电位幅度的反弹增加以及起搏周期长度的缩短。在存在2 mmol/L铯（I(f)的阻滞剂）的情况下，撤除ACh所引发的起搏周期长度的反弹缩短未改变。我们得出结论，在SAN和LAP细胞中，撤除ACh主要通过cAMP介导的ICa,L反弹刺激引发正性变时反应。这些发现首次证明了一种可能直接促成迷走神经节后心动过速非肾上腺素能成分的内在细胞机制。
