Banerjee A, Locke-Winter C, Rogers K B, Mitchell M B, Brew E C, Cairns C B, Bensard D D, Harken A H
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262.
Circ Res. 1993 Oct;73(4):656-70. doi: 10.1161/01.res.73.4.656.
Preconditioning may find ready applicability in humans facing scheduled global cardiac ischemia-reperfusion (IR) during bypass or transplantation, where such a maneuver is feasible before arrest. Our objective was to delineate and exploit the endogenous preconditioning mechanism triggered by transient ischemia (TI) and thereby attenuate myocardial postischemic mechanical dysfunction by clinically acceptable means. Preconditioning by 2 minutes of TI followed by 10 minutes of normal perfusion protected isolated rat left ventricle function assessed after 20 minutes of global, 37 degrees C ischemia and 40 minutes of reperfusion. Final recovery of developed pressure (DP) was improved (91.5 +/- 1.9% of equilibration DP versus unconditioned IR control, 57.4 +/- 2.4%, P < .01) and was accompanied by increased contractility (+/- dP/dt). Norepinephrine release increased after TI, and reserpine pretreatment abolished TI preconditioning. This suggests that endogenous norepinephrine mediates functional preconditioning in rat. Brief pretreatment (2 minutes) with exogenous norepinephrine reproduced the protection (89.1 +/- 1.4%) of postischemic function. Functional protection persisted after the hemodynamic effects had resolved. Norepinephrine-induced preconditioning was simulated by phenylephrine and blocked by alpha 1-adrenergic receptor antagonist. TI preconditioning was similarly lost after selective alpha 1-adrenergic receptor blockade. We conclude that transient ischemic preconditioning is mediated by the sympathetic neurotransmitter release and alpha 1-adrenergic receptor stimulation. Although the postreceptor mechanism remains unclear, functional protection after IR does not seem related to the magnitude of ATP depletion and elevation of resting pressure during ischemia. Rather, the endogenous mechanisms facilitate both recovery of mechanical function and ATP repletion during reperfusion.
预处理可能会在接受心脏搭桥或移植手术时面临计划性全心脏缺血-再灌注（IR）的患者中得到实际应用，因为在心脏停搏前进行这种操作是可行的。我们的目标是阐明并利用由短暂性缺血（TI）触发的内源性预处理机制，从而通过临床上可接受的方法减轻心肌缺血后机械功能障碍。通过2分钟的TI预处理，随后进行10分钟的正常灌注，可保护离体大鼠左心室功能，该功能在37℃全心脏缺血20分钟和再灌注40分钟后进行评估。舒张末压力（DP）的最终恢复得到改善（预处理组为平衡DP的91.5±1.9%，未预处理的IR对照组为57.4±2.4%，P<0.01），并伴有收缩力增加（±dP/dt）。TI后去甲肾上腺素释放增加，利血平预处理可消除TI预处理。这表明内源性去甲肾上腺素介导大鼠的功能性预处理。用外源性去甲肾上腺素进行短暂预处理（2分钟）可重现对缺血后功能的保护作用（89.1±1.4%）。血流动力学效应消退后，功能保护仍然存在。苯肾上腺素可模拟去甲肾上腺素诱导的预处理，而α1-肾上腺素能受体拮抗剂可阻断该作用。选择性α1-肾上腺素能受体阻断后，TI预处理同样消失。我们得出结论，短暂性缺血预处理是由交感神经递质释放和α1-肾上腺素能受体刺激介导的。尽管受体后机制尚不清楚，但IR后的功能保护似乎与缺血期间ATP消耗的程度和静息压力的升高无关。相反，内源性机制促进了再灌注期间机械功能的恢复和ATP的补充。
