Yasutake M, Avkiran M
Rayne Institute, St Thomas' Hospital, London, United Kingdom.
Cardiovasc Res. 1995 Feb;29(2):222-30.
Stimulation of myocardial alpha 1 adrenoceptors causes (1) exacerbation of reperfusion induced arrhythmias, and (2) stimulation of sarcolemmal Na+/H+ exchange. The aims of this study were to identify the alpha 1 adrenoceptor subtype involved in the former effect and to determine whether stimulation of the Na+/H+ exchanger may play a role in this phenomenon.
Isolated rat hearts were subjected to independent perfusion of the left and right coronary beds. After 15 min of aerobic perfusion of both beds, the alpha 1 adrenoceptor agonist phenylephrine (0.1, 1, or 10 microM) was infused selectively into the left coronary bed for 2 min. The left coronary bed was then subjected to 7 min of zero flow ischaemia and 5 min of reperfusion.
The incidence of reperfusion induced ventricular fibrillation was increased from 0% in controls to 8%, 42%, and 75% with 0.1, 1, and 10 microM phenylephrine (P < 0.05); this dose dependent effect occurred in the absence of significant intergroup differences in vascular resistance or heart rate. Similar infusion of methoxamine at 10 microM also increased the incidence of reperfusion induced ventricular fibrillation from 13% to 88%. Infusion of 10 microM phenylephrine during reperfusion alone did not affect the incidence of reperfusion induced ventricular fibrillation. Infusion of the selective alpha 1A adrenoceptor antagonist WB4101 at 0.1, 1, or 10 microM for 2 min immediately before ischaemia (concomitantly with 10 microM phenylephrine) reduced the incidence of reperfusion induced ventricular fibrillation from 83% to 75%, 25%, and 0%. Similar infusion of the selective alpha 1B adrenoceptor antagonist chloroethylclonidine (0.1 or 1 microM) or the selective beta 1 adrenoceptor antagonist atenolol (0.1 or 1 microM) did not reduce the incidence of reperfusion induced ventricular fibrillation. The novel NHE-1 selective Na+/H+ exchange inhibitor HOE694 (10 microM), when infused into the left coronary bed before ischaemia (concomitantly with 10 microM phenylephrine) and throughout reperfusion, reduced the incidence of reperfusion induced ventricular fibrillation from 83% to 25%*. In hearts that received 10 microM phenylephrine before ischaemia. HOE694 (10 microM) was partially effective when infused during reperfusion alone (ventricular fibrillation incidence reduced from 83% to 42%).
(1) the exacerbation of reperfusion induced arrhythmias by alpha 1 adrenergic stimulation during ischaemia is mediated by the alpha 1A adrenoceptor subtype, and (2) increased Na+/H+ exchanger activity during ischaemia and reperfusion may play a causal role in this phenomenon.
刺激心肌α1肾上腺素能受体可导致：（1）再灌注诱导的心律失常加重；（2）刺激肌膜钠/氢交换。本研究的目的是确定参与前一种效应的α1肾上腺素能受体亚型，并确定刺激钠/氢交换体是否可能在这一现象中起作用。
将离体大鼠心脏的左、右冠状动脉床进行独立灌注。在对两个冠状动脉床进行15分钟有氧灌注后，将α1肾上腺素能受体激动剂去氧肾上腺素（0.1、1或10微摩尔）选择性注入左冠状动脉床2分钟。然后左冠状动脉床进行7分钟的零流量缺血和5分钟的再灌注。
再灌注诱导的心室颤动发生率从对照组的0%分别增加到0.1、1和10微摩尔去氧肾上腺素时的8%、42%和75%（P<0.05）；这种剂量依赖性效应在血管阻力或心率组间无显著差异的情况下出现。以10微摩尔类似剂量注入甲氧明也使再灌注诱导的心室颤动发生率从13%增加到88%。仅在再灌注期间注入10微摩尔去氧肾上腺素不影响再灌注诱导的心室颤动发生率。在缺血前（与10微摩尔去氧肾上腺素同时）立即注入0.1、1或10微摩尔选择性α1A肾上腺素能受体拮抗剂WB4101 2分钟，可使再灌注诱导的心室颤动发生率从83%分别降低到75%、25%和0%。类似地注入选择性α1B肾上腺素能受体拮抗剂氯乙可乐定（0.1或1微摩尔）或选择性β1肾上腺素能受体拮抗剂阿替洛尔（0.1或1微摩尔）并未降低再灌注诱导的心室颤动发生率。新型NHE-1选择性钠/氢交换抑制剂HOE694（10微摩尔），在缺血前（与10微摩尔去氧肾上腺素同时）注入左冠状动脉床并在整个再灌注过程中持续注入，可使再灌注诱导的心室颤动发生率从83%降低到25%*。在缺血前接受10微摩尔去氧肾上腺素的心脏中，仅在再灌注期间注入HOE694（10微摩尔）有部分效果（心室颤动发生率从83%降低到42%）。
（1）缺血期间α1肾上腺素能刺激使再灌注诱导的心律失常加重是由α1A肾上腺素能受体亚型介导的；（2）缺血和再灌注期间钠/氢交换体活性增加可能在这一现象中起因果作用。
