Intracellular calcium dynamics and acceleration of sinus rhythm by beta-adrenergic stimulation.
Intracellular calcium dynamics and acceleration of sinus rhythm by beta-adrenergic stimulation.
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DOI：
10.1161/circulationaha.108.817379
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发表时间：
2009-02-17
期刊：
影响因子：
37.8
通讯作者：
Lin SF
中科院分区：
文献类型：
--
作者：
Joung B;Tang L;Maruyama M;Han S;Chen Z;Stucky M;Jones LR;Fishbein MC;Weiss JN;Chen PS;Lin SF
最近的证据表明，膜电压和钙时钟共同调节窦房结（SAN）的自律性。在这里，我们测试的假设，窦率加速β-肾上腺素能刺激涉及这些时钟机制之间的协同作用。我们同时映射细胞内钙（Cai）和膜电位（Vm）在25个离体犬右心房（RA），使用先前描述的标准的时间舒张晚期Cai升高（LDCAE）相对于动作电位（AP）上行程检测钙时钟。在使用异丙肾上腺素之前，最早的起搏部位发生在下SAN，仅在4/25份制剂中观察到LDCAE。异丙肾上腺素（1 μmol/L）可增加窦性心率，使起搏部位移向上级SAN，同时在AP上升前98 ± 31 ms出现LDCAE。咖啡因具有类似的作用，而用ryanodine和thapsigargin耗竭SR Ca 2+可防止异丙肾上腺素诱导的LDCAE，并使窦性心率加速减弱。ISO期间，上级SAN（124 ± 34 ms）的CAI瞬时松弛时间短于下级SAN（138 ± 24 ms，p = 0.01）或RA（164 ± 33 ms，p = 0.001），并且与SAN中SR Ca 2 + ATP酶泵与受磷蛋白的比率低于RA相关。ZD 7288的电流阻断作用适度减弱，但不能阻止LDCAE或异丙肾上腺素引起的窦性心率加快。上级SAN中Ca 2+时钟的加速在β-肾上腺素能刺激期间的窦加速中起重要作用，与电压时钟协同作用以增加窦率。
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 β-adrenergic stimulation involves synergistic interactions between these clock mechanisms. We simultaneously mapped intracellular calcium (Cai) and membrane potential (Vm) in 25 isolated canine right atrium (RA), using previously described criteria of the timing of late diastolic Cai elevation (LDCAE) relative to the action potential (AP) upstroke to detect the Ca2+ clock. Before isoproterenol, the earliest pacemaking site occurred in the inferior SAN, and LDCAE was observed in only 4/25 preparations. Isoproterenol (1 μmol/L) increased sinus rate and shifted pacemaking site to superior SAN, concomitant with the appearance of LDCAE preceding the AP upstroke by 98 ± 31 ms. Caffeine had similar effects, while SR Ca2+ depletion with ryanodine and thapsigargin prevented isoproterenol-induced LDCAE and blunted sinus rate acceleration. Cai transient relaxation time during ISO was shorter in superior SAN (124 ± 34 ms) than inferior SAN (138 ± 24 ms, p = 0.01) or RA (164 ± 33 ms, p = 0.001), and was associated with a lower SR Ca2+ ATPase pump to phospholamban protein ratio in SAN than in RA. If current 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 β-adrenergic stimulation, interacting synergistically with the voltage clock to increase sinus rate.