Joung Boyoung, Tang Liang, Maruyama Mitsunori, Han Seongwook, Chen Zhenhui, Stucky Marcelle, Jones Larry R, Fishbein Michael C, Weiss James N, Chen Peng-Sheng, Lin Shien-Fong
Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
Circulation. 2009 Feb 17;119(6):788-96. doi: 10.1161/CIRCULATIONAHA.108.817379. Epub 2009 Feb 2.
Recent evidence indicates that membrane voltage and Ca2+ clocks jointly regulate sinoatrial node (SAN) automaticity. Here we test the hypothesis that sinus rate acceleration by beta-adrenergic stimulation involves synergistic interactions between these clock mechanisms.
We simultaneously mapped intracellular calcium (Ca(i)) and membrane potential in 25 isolated canine right atrium, using previously described criteria of the timing of late diastolic Ca(i) elevation (LDCAE) relative to the action potential upstroke to detect the Ca2+ clock. Before isoproterenol, the earliest pacemaking site occurred in the inferior SAN, and LDCAE was observed in only 4 of 25 preparations. Isoproterenol infusion (1 micromol/L) increased sinus rate and shifted pacemaking site to superior SAN, concomitant with the appearance of LDCAE preceding the action potential upstroke by 98+/-31 ms. Caffeine had similar effects, whereas sarcoplasmic reticulum Ca2+ depletion with ryanodine and thapsigargin prevented isoproterenol-induced LDCAE and blunted sinus rate acceleration. Ca(i) transient relaxation time during isoproterenol was shorter in superior SAN (124+/-34 ms) than inferior SAN (138+/-24 ms; P=0.01) or right atrium (164+/-33 ms; P=0.001) and was associated with a lower sarcoplasmic reticulum Ca2+ ATPase pump to phospholamban protein ratio in SAN than in right atrium. Hyperpolarization-activated pacemaker current (I(f)) blockade with ZD 7288 modestly blunted but did not prevent LDCAE or sinus rate acceleration by isoproterenol.
Acceleration of the Ca2+ clock in the superior SAN plays an important role in sinus acceleration during beta-adrenergic stimulation, interacting synergistically with the voltage clock to increase sinus rate.
最近的证据表明，膜电压和Ca2+时钟共同调节窦房结（SAN）的自律性。在此，我们检验以下假设：β-肾上腺素能刺激引起的窦性心率加速涉及这些时钟机制之间的协同相互作用。
我们使用先前描述的舒张晚期Ca(i)升高（LDCAE）相对于动作电位上升支的时间标准，在25个离体犬右心房中同时记录细胞内钙（Ca(i)）和膜电位，以检测Ca2+时钟。在异丙肾上腺素给药前，最早的起搏部位出现在SAN下部，25个标本中只有4个观察到LDCAE。输注异丙肾上腺素（1 μmol/L）可增加窦性心率，并使起搏部位转移至SAN上部，同时出现动作电位上升支之前98±31 ms的LDCAE。咖啡因有类似作用，而用ryanodine和毒胡萝卜素使肌浆网Ca2+耗竭可阻止异丙肾上腺素诱导的LDCAE，并减弱窦性心率加速。异丙肾上腺素作用期间，SAN上部的Ca(i)瞬变松弛时间（124±34 ms）短于SAN下部（138±24 ms；P=0.01）或右心房（164±33 ms；P=0.001），且与SAN中肌浆网Ca2+ATP酶泵与受磷蛋白的比值低于右心房有关。用ZD 7288阻断超极化激活起搏电流（I(f)）可适度减弱但不能阻止异丙肾上腺素引起的LDCAE或窦性心率加速。
SAN上部Ca2+时钟的加速在β-肾上腺素能刺激期间的窦性加速中起重要作用，与电压时钟协同作用以增加窦性心率。
