Monnet X, Ghaleh B, Colin P, de Curzon O P, Giudicelli J F, Berdeaux A
Laboratoire de Pharmacologie, Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
J Pharmacol Exp Ther. 2001 Dec;299(3):1133-9.
We investigated the effects of the selective bradycardic agent ivabradine, an I(f) channel inhibitor, on exercise-induced ischemia and resulting myocardial stunning. Seven dogs were chronically instrumented to measure left ventricular (LV) wall thickening (Wth), aortic pressure and coronary blood flow (CBFv) (Doppler). Circumflex coronary artery stenosis was set up to suppress the increase in CBFv during a 10 min treadmill exercise. During exercise under saline, LVWth in the ischemic zone was depressed (-70 +/- 4%) and a prolonged myocardial stunning was subsequently observed. Infusion of ivabradine started before exercise significantly reduced heart rate (HR) at rest (-22 +/- 7%), during exercise (-33 +/- 4%) and throughout the recovery period (-21 +/- 2%). By reducing HR during exercise, ivabradine simultaneously improved LVWth compared with saline (14 +/- 1% versus 7 +/- 1%, respectively) and subendocardial perfusion (microspheres). This anti-ischemic effect was subsequently responsible for a strong decrease in the intensity and severity of myocardial stunning. All these beneficial effects were abolished when HR reduction during exercise was suppressed by atrial pacing. Interestingly, when ivabradine infusion was started after exercise, LVWth was still significantly enhanced and myocardial stunning strongly attenuated. This direct effect of ivabradine on the stunned myocardium disappeared when HR reduction was suppressed by atrial pacing at rest. In conclusion, this study demonstrates that ivabradine exerts an anti-ischemic effect that is responsible for subsequent protection against myocardial stunning. Furthermore, administration of ivabradine after the ischemic insult still improves LVWth of the stunned myocardium.
我们研究了选择性心动过缓药物伊伐布雷定（一种I(f)通道抑制剂）对运动诱发的心肌缺血及由此导致的心肌顿抑的影响。对7只犬进行长期仪器植入，以测量左心室（LV）壁增厚（Wth）、主动脉压力和冠状动脉血流（CBFv）（多普勒测量）。通过设置左旋冠状动脉狭窄来抑制10分钟跑步机运动期间CBFv的增加。在生理盐水输注下运动时，缺血区的LVWth降低（-70±4%），随后观察到心肌顿抑时间延长。在运动前开始输注伊伐布雷定可显著降低静息心率（HR）（-22±7%）、运动期间心率（-33±4%）以及整个恢复期间的心率（-21±2%）。通过在运动期间降低心率，与生理盐水相比，伊伐布雷定同时改善了LVWth（分别为14±1%和7±1%）以及心内膜下灌注（微球测量）。这种抗缺血作用随后导致心肌顿抑的强度和严重程度大幅降低。当通过心房起搏抑制运动期间的心率降低时，所有这些有益作用均消失。有趣的是，当在运动后开始输注伊伐布雷定时，LVWth仍显著增强，心肌顿抑也明显减轻。当静息时通过心房起搏抑制心率降低时，伊伐布雷定对顿抑心肌的这种直接作用消失。总之，本研究表明伊伐布雷定发挥抗缺血作用，从而对心肌顿抑起到后续保护作用。此外，在缺血损伤后给予伊伐布雷定仍可改善顿抑心肌的LVWth。
