Shinohara Tetsuji, Kim Daehyeok, Joung Boyoung, Maruyama Mitsunori, Vembaiyan Kannan, Back Thomas G, Wayne Chen S R, Chen Peng-Sheng, Lin Shien-Fong
Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, 1801 N. Capitol Ave, E 308, Indianapolis, IN, 46202, USA.
Heart Vessels. 2014 May;29(3):396-403. doi: 10.1007/s00380-013-0378-2. Epub 2013 Jul 9.
The membrane voltage clock and calcium (Ca(2+)) clock jointly regulate sinoatrial node (SAN) automaticity. VK-II-36 is a novel carvedilol analog that suppresses sarcoplasmic reticulum (SR) Ca(2+) release but does not block the β-receptor. The effect of VK-II-36 on SAN function remains unclear. The purpose of this study was to evaluate whether VK-II-36 can influence SAN automaticity by inhibiting the Ca(2+) clock. We simultaneously mapped intracellular Ca(2+) and membrane potential in 24 isolated canine right atriums using previously described criteria of the timing of late diastolic intracellular Ca elevation (LDCAE) relative to the action potential upstroke to detect the Ca(2+) clock. Pharmacological interventions with isoproterenol (ISO), ryanodine, caffeine, and VK-II-36 were performed after baseline recordings. VK-II-36 caused sinus rate downregulation and reduced LDCAE in the pacemaking site under basal conditions (P < 0.01). ISO induced an upward shift of the pacemaking site in SAN and augmented LDCAE in the pacemaking site. ISO also significantly and dose-dependently increased the sinus rate. The treatment of VK-II-36 (30 μmol/l) abolished both the ISO-induced shift of the pacemaking site and augmentation of LDCAE (P < 0.01), and it suppressed the ISO-induced increase in sinus rate (P = 0.02). Our results suggest that the sinus rate may be partly controlled by the Ca(2+) clock via SR Ca(2+) release during β-adrenergic stimulation.
膜电压时钟和钙（Ca(2+)）时钟共同调节窦房结（SAN）的自律性。VK-II-36是一种新型的卡维地洛类似物，可抑制肌浆网（SR）Ca(2+)释放，但不阻断β受体。VK-II-36对SAN功能的影响尚不清楚。本研究的目的是评估VK-II-36是否能通过抑制Ca(2+)时钟来影响SAN自律性。我们使用先前描述的舒张晚期细胞内Ca升高（LDCAE）相对于动作电位上升支的时间标准，在24个离体犬右心房中同时记录细胞内Ca(2+)和膜电位，以检测Ca(2+)时钟。在基线记录后，用异丙肾上腺素（ISO）、ryanodine、咖啡因和VK-II-36进行药物干预。在基础条件下，VK-II-36导致起搏部位的窦性心率下调并降低LDCAE（P < 0.01）。ISO引起SAN起搏部位上移，并增加起搏部位的LDCAE。ISO还显著且剂量依赖性地增加窦性心率。VK-II-36（30 μmol/l）处理消除了ISO诱导的起搏部位移位和LDCAE增加（P < 0.01），并抑制了ISO诱导的窦性心率增加（P = 0.02）。我们的结果表明，在β肾上腺素能刺激期间，窦性心率可能部分受Ca(2+)时钟通过SR Ca(2+)释放的控制。
