Canyon Sarah J, Dobson Geoffrey P
Department of Physiology and Pharmacology, James Cook University, Queensland, Australia.
J Thorac Cardiovasc Surg. 2005 Aug;130(2):371-7. doi: 10.1016/j.jtcvs.2004.12.052.
The heart possesses an extraordinary ability to remember short episodes of sublethal ischemia and reperfusion (angina), which protects the myocardium and coronary vasculature from a subsequent lethal insult, a phenomenon known as ischemic preconditioning. A therapeutic goal for more than 2 decades has been to develop a pharmacologic mimetic comparable with ischemic preconditioning. Our aim was to investigate the preconditioning effect of a new combinatorial therapy targeting adenosine A1 receptors and voltage-dependent sodium fast channels in the in vivo rat model of regional ischemia.
Ischemia-reperfusion was achieved by placing a reversible tie around the left coronary artery in anesthetized and ventilated Sprague-Dawley rats (n = 37). Rats were randomly assigned to 1 of 5 groups: (1) saline control (n = 13); (2) ischemic preconditioning (n = 6); (3) lidocaine only (608 microg . kg -1 . min -1 , n = 5); (4) adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 5 microg/kg, n = 7); and (5) CCPA plus lidocaine (n = 6). Ischemic preconditioning was achieved by using 3 cycles of ischemia and reperfusion lasting 3 minutes each. Lidocaine was infused continuously 5 minutes before and throughout 30 minutes of ischemia and ceased at reperfusion. A bolus of CCPA was infused 5 minutes before ligation along with a constant infusion of lidocaine (as above). All animals were reperfused for 120 minutes for infarct size measurement.
Fifty-four percent of saline control rats, 17% of ischemic preconditioning-treated rats, and 29% of CCPA-treated rats died during ischemia from ventricular fibrillation. Infarct size of saline control animals was 61% +/- 5%. Pretreating with CCPA and lidocaine infusion resulted in no deaths, no severe arrhythmias, and significant infarct size reduction compared with that seen in saline control animals (P < .05). Remarkably, infarct size reduction in CCPA plus lidocaine-treated rats (12% +/- 4%) was equivalent to that achieved with ischemic preconditioning (11% +/- 3%), whereas infarct size in rats undergoing CCPA-only and lidocaine-only treatments was 42% +/- 7% and 60% +/- 6%, respectively. Although CCPA plus lidocaine treatment reduced heart rate, mean arterial pressure, and systolic pressure during ischemia, no correlation was found between these variables and infarct size reduction.
We conclude that activating adenosine A1 receptor subtype with CCPA and concomitantly modulating sodium fast channels with lidocaine was comparable with ischemic preconditioning and might offer a new therapeutic window to minimize myocardial damage during surgical ischemia and reperfusion.
心脏具有一种非凡的能力，能够记住亚致死性缺血和再灌注（心绞痛）的短暂发作，这可保护心肌和冠状血管免受随后的致死性损伤，这种现象称为缺血预处理。二十多年来的一个治疗目标是开发一种与缺血预处理相当的药物模拟物。我们的目的是在局部缺血的体内大鼠模型中研究一种靶向腺苷A1受体和电压依赖性快速钠通道的新联合疗法的预处理效果。
通过在麻醉并通气的Sprague-Dawley大鼠（n = 37）的左冠状动脉周围放置一个可逆的结扎来实现缺血再灌注。将大鼠随机分为5组中的1组：（1）生理盐水对照组（n = 13）；（2）缺血预处理组（n = 6）；（3）仅利多卡因组（608μg·kg-1·min-1，n = 5）；（4）腺苷A1受体激动剂2-氯-N6-环戊基腺苷（CCPA；5μg/kg，n = 7）；和（5）CCPA加利多卡因组（n = 6）。通过使用3个持续3分钟的缺血和再灌注周期来实现缺血预处理。在缺血前5分钟和整个30分钟缺血期间持续输注利多卡因，并在再灌注时停止。在结扎前5分钟推注CCPA并同时持续输注利多卡因（如上所述）。所有动物再灌注120分钟以测量梗死面积。
生理盐水对照组中54%的大鼠、缺血预处理组中17%的大鼠和CCPA处理组中29%的大鼠在缺血期间死于心室颤动。生理盐水对照动物的梗死面积为61%±5%。与生理盐水对照动物相比，用CCPA和利多卡因输注进行预处理未导致死亡、未出现严重心律失常，且梗死面积显著减小（P <.05）。值得注意的是，CCPA加利多卡因处理的大鼠的梗死面积减小（12%±4%）与缺血预处理所达到的梗死面积减小（11%±3%）相当，而仅接受CCPA和仅接受利多卡因治疗的大鼠的梗死面积分别为42%±7%和60%±6%。尽管CCPA加利多卡因治疗在缺血期间降低了心率、平均动脉压和收缩压，但未发现这些变量与梗死面积减小之间存在相关性。
我们得出结论，用CCPA激活腺苷A1受体亚型并同时用利多卡因调节快速钠通道与缺血预处理相当，可能为在手术缺血和再灌注期间最小化心肌损伤提供一个新的治疗窗口。
