Tissier Renaud, Aouam Karim, Berdeaux Alain, Ghaleh Bijan
Laboratoire de Pharmacologie, Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine Paris-Sud, Bicêtre, France.
J Pharmacol Exp Ther. 2003 Aug;306(2):528-31. doi: 10.1124/jpet.103.052563. Epub 2003 May 2.
Although extensive attention has been devoted to the window of preconditioning, only few studies investigated the efficacy of preconditioning against ischemia with increasing durations. To date, a "ceiling of protection" has been demonstrated to occur with early preconditioning but nothing is known about delayed preconditioning. Accordingly, the efficacy of a nitric oxide (NO)-donor-induced delayed preconditioning was tested against ischemic insults of increasing duration. Accordingly, 65 rabbits received a 75-min intravenous infusion of either saline (control group), or an NO-donor (S-nitroso-N-acetylpenicillamine) at 3 microg/kg/min (SNAP-3 group) or 30 microg/kg/min (SNAP-30 group). Twenty-four hours later, rabbits randomly underwent either a 15-, 20-, or a 30-min coronary artery occlusion (CAO). Infarct size was assessed after 72-h reperfusion (triphenyltetrazolium chloride staining, percentage of the area at risk). After 15-min CAO, both SNAP-3 and SNAP-30 reduced infarct size compared with control (10 +/- 3, 5 +/- 1 versus 29 +/- 8%, respectively; p < 0.05). After 20-min CAO, significant cardioprotection was only observed with SNAP-30 (29 +/- 4, 21 +/- 6 versus 36 +/- 2% for SNAP-3, SNAP-30 versus control, respectively). After 30-min CAO, both SNAP-3 and SNAP-30 failed to reduce infarct size (48 +/- 2, 50 +/- 5 versus 50 +/- 4% for SNAP-3, SNAP-30 versus control, respectively). In conclusion, this study demonstrates a dose-related ceiling of protection with delayed preconditioning induced by an NO donor. It supports that delayed preconditioning might exert its maximal beneficial effect with early reperfusion and this finding supports the necessary use of different durations of ischemia when investigating cardioprotective strategies.
尽管对预处理的时间窗已给予了广泛关注，但仅有少数研究探讨了随着预处理持续时间增加其抗缺血的效果。迄今为止，已证实早期预处理会出现“保护上限”，但对于延迟预处理却一无所知。因此，测试了一氧化氮（NO）供体诱导的延迟预处理对抗持续时间不断增加的缺血损伤的效果。相应地，65只兔子接受了75分钟的静脉输注，其中一组输注生理盐水（对照组），另外两组分别以3微克/千克/分钟（SNAP - 3组）或30微克/千克/分钟（SNAP - 30组）的速度输注NO供体（S - 亚硝基 - N - 乙酰青霉胺）。24小时后，兔子随机接受15分钟、20分钟或30分钟的冠状动脉闭塞（CAO）。在72小时再灌注后评估梗死面积（用氯化三苯基四氮唑染色，计算危险区域面积的百分比）。在15分钟CAO后，与对照组相比，SNAP - 3组和SNAP - 30组的梗死面积均减小（分别为10±3、5±1与29±8%；p<0.05）。在20分钟CAO后，仅在SNAP - 30组观察到显著的心脏保护作用（SNAP - 3组、SNAP - 30组与对照组的梗死面积分别为为29±4、21±6与36±2%）。在30分钟CAO后，SNAP - 3组和SNAP - 30组均未能减小梗死面积（SNAP - 3组、SNAP - 30组与对照组的梗死面积分别为48±2、50±5与50±4%）。总之，本研究证明了NO供体诱导的延迟预处理存在剂量相关的保护上限。这支持了延迟预处理可能在早期再灌注时发挥其最大有益作用，并且这一发现支持在研究心脏保护策略时使用不同持续时间的缺血的必要性。
