Jia D, Yasutake M, Kusama Y, Kishida H, Hayakawa H
First Department of Medicine, Nippon Medical School, Tokyo, Japan.
Nihon Ika Daigaku Zasshi. 1998 Aug;65(4):276-83. doi: 10.1272/jnms1923.65.276.
Stimulation of receptors for alpha 1-adrenergic agonist, endothelin (ET) and angiotensin II (AT) activates the cardiac sarcolemmal Na+/H+ exchanger (NHE), perhaps via protein kinase C(PKC)-mediated pathway(s). We tested for the ability of these extracellular stimuli to exacerbate reperfusion arrhythmias and for the possible role of NHE activation and PKC in such phenomena. Isolated rat hearts (n = 12/group) were subjected to dual coronary perfusion. After 15 min of aerobic perfusion, flow to the left coronary bed was reduced to 5% of basal values for 12 min, and the same bed was then reperfused for 5 min. An alpha 1-adrenergic agonist phenylephrine (PE) at 1 or 10 mumol/L, ET at 0.5 or 5nmol/L or AT at 1 or 10mumol/L was infused selectively into the left coronary bed during 12 min of regional low flow ischemia. The incidence of reperfusion-induced ventricular fibrillation (VF) was increased from 17% in control to 33% and 75%* with 1 and 10 mumol/L PE(p < 0.05 vs control) from 8% in control to 8% and 12% with 0.5 and 5 nmol/L of ET. However, AT had no effect. The selective NHE inhibitor NOE642 at 1 mumol/L, infused concomitantly with 10 mumol/L PE, reversed the proarrhythmic effects of PE; VF incidence was reduced from 67% to 8%. However, glibenclamide (a blocker for the ATP-sensitive K+ channel) at 1 mumol/L did not affect the proarrhythmic effects of PE. Infusion of a specific PKC inhibitor GF109203X(GF) at 30 or 300 nmol/L, starting from 5 min before ischemia and maintained throughout ischemia concomitantly with 10 mumol/L of PE, was partially effective in reducing VF incidence; which reduced from 75% in control to 42% with 300 nmol/L of GF. These results suggest that, in rat hearts subjected to regional low-flow ischemia and reperfusion, stimulation of alpha 1-adrenergic receptor can exacerbate reperfusion-induced VF, whose mechanism(s) may involve NHE activation. Moreover, PKC activation does not appear to be the sole signaling mechanism for this phenomenon.
α1 - 肾上腺素能激动剂、内皮素（ET）和血管紧张素 II（AT）的受体刺激可激活心肌肌膜钠/氢交换体（NHE），可能是通过蛋白激酶 C（PKC）介导的途径。我们测试了这些细胞外刺激加剧再灌注心律失常的能力以及NHE激活和PKC在此类现象中的可能作用。将离体大鼠心脏（每组 n = 12）进行双冠状动脉灌注。在有氧灌注 15 分钟后，左冠状动脉床的血流量降至基础值的 5%，持续 12 分钟，然后对同一床进行 5 分钟的再灌注。在局部低流量缺血的 12 分钟内，将 1 或 10 μmol/L 的α1 - 肾上腺素能激动剂去氧肾上腺素（PE）、0.5 或 5 nmol/L 的 ET 或 1 或 10 μmol/L 的 AT 选择性注入左冠状动脉床。再灌注诱导的心室颤动（VF）发生率从对照组的 17%分别增加到 1 和 10 μmol/L PE 组的 33%和 75%（与对照组相比，p < 0.05），从对照组的 8%分别增加到 0.5 和 5 nmol/L ET 组的 8%和 12%。然而，AT 没有影响。与 10 μmol/L PE 同时注入 1 μmol/L 的选择性 NHE 抑制剂 NOE642 可逆转 PE 的促心律失常作用；VF 发生率从 67%降至 8%（）。然而，1 μmol/L 的格列本脲（一种 ATP 敏感性钾通道阻滞剂）对 PE 的促心律失常作用没有影响。从缺血前 5 分钟开始，持续至整个缺血过程，与 10 μmol/L 的 PE 同时注入 30 或 300 nmol/L 的特异性 PKC 抑制剂 GF109203X（GF），在降低 VF 发生率方面部分有效；从对照组的 75%降至 300 nmol/L GF 组的 42%。这些结果表明，在经历局部低流量缺血和再灌注的大鼠心脏中，α1 - 肾上腺素能受体的刺激可加剧再灌注诱导的 VF，其机制可能涉及 NHE 激活。此外，PKC 激活似乎不是这一现象的唯一信号传导机制。
