ENDOGENOUS PRECONDITIONING PROTECTS AGAINST SHOCK

重大创伤伴随着内分泌反应，这种反应在一定程度上是由 通过交感神经系统。交感肾上腺素能刺激促进 通过改变血流动力学在应激情况下存活(加压 影响)和创伤后系统代谢(协调葡萄糖 对基本器官的供应)。我们的调查显示还有 促进末梢器官对后续休克的耐受性的有益效果 (缺血再灌注，IR)。这种后续损伤的减弱是 被称为预适应，似乎是通过AE1肾上腺素能调节的 感受器。有趣的是，我们发现瞬变冲击本身 作为预适应信号，但仅当它在持续之前 休克(缺血)几分钟。然而突如其来的创伤可能不允许 预适应信号和缺血之间的先决条件延迟。 因此，这项提议的目标是描述预条件 赋予耐受性的机制，所以这其中的最后一步 在持续休克期间或之后可激活内源性级联反应 提高存活率。 我们使用模型研究了这种保护现象，其中 预适应首先被记录下来(大鼠心脏)。最近有报道称 骨骼肌和游离皮瓣的预适应提示了这一点 保护可以在多个器官中诱导。心很是痛 易受IR损伤，这是可重复量化的。这个 心脏肾上腺素能受体和信号转导通路有很多 与其他末端器官中的途径相同，但具有优势 在生化、药理和功能上都更好 特色化的。我们的证据表明，短暂性休克引起局部 释放交感神经递质去甲肾上腺素 通过刺激突触后α1肾上腺素能受体进行预适应。 去甲肾上腺素诱导的预适应不是由升压引起的 效果。相反，我们的初步结果表明，预适应 涉及由肾上腺素能途径介导的代谢变化 持久的，即使在变力和变时性效应之后 完全解决了。而缺血再灌注损伤线粒体 氧摄取、预适应可防止这种损害并增强ATP 重新合成。替代短暂性脑缺血引起的去甲肾上腺素释放 休克、预适应可通过短暂输注外源性 去甲肾上腺素。远端刺激AE1肾上腺素能通路将 允许在不增加终末器官氧气需求的情况下进行预适应 去甲肾上腺素引起的血管阻力增加。因此， 这项建议的目的是：1.描述预适应 短暂性休克(短暂性脑缺血，TI)对END恢复的影响 随后的缺血后的器官功能(离体心)- 再灌注性损伤。2.调查同情者的角色 神经递质去甲肾上腺素(NE)在预适应中的作用 由短暂性脑缺血引起。3.调查 去甲肾上腺素诱导的转导预适应的肾上腺素能通路。4. 研究缺血代谢物--腺苷在介导 TI或AE1通路诱导的预适应。5.描述 上调能量代谢是预适应的基础。

Major trauma is accompanied by an endocrine response, mediated in part by the sympathetic system. Sympathetic adrenergic stimulation promotes survival in stressful situations by altering hemodynamics (pressor effect) and post-traumatic systemic metabolism (coordinating glucose supply to essential organs). Our investigations indicate an additional beneficial effect that promotes end organ tolerance to subsequent shock (ischemia-reperfusion, IR). this attenuation of subsequent injury is termed preconditioning and appears to be mediated via ae1 adrenergic receptors. Interestingly we have found that transient shock itself serves as preconditioning signal, but only if it precedes sustained shock (ischemia) by a few minutes. However sudden trauma may not permit the prerequisite delay between the preconditioning signal and ischemia. therefore the goal of this proposal is to delineate the preconditioning mechanisms conferring tolerance, so that a distal step in this endogenous cascade can be activated during or after sustained shock to improve survival. We have investigated this protective phenomenon using the model where preconditioning was first documented (rat heart). Recent reports of preconditioning in skeletal muscle and free-flaps suggest this protection is inducible in multiple organs. The heart is very vulnerable to IR injury which can be reproducibly quantified. The cardiac adrenergic receptors and signal transduction pathways have much in common with the pathways in other end-organs, but have the advantage of being biochemically, pharmacologically and functionally better characterized. Our evidence suggests that transient shock elicits local release of the sympathetic neurotransmitter, norepinephrine which preconditions by stimulating post-synaptic alpha1 adrenergic receptors. Norepinephrine induced preconditioning is not due to its pressor effects. Rather, our preliminary results indicate that preconditioning involves metabolic changes mediated by the adrenergic pathway which are persistent, even after inotropic and chronotropic effects have completely resolved. whereas ischemia-reperfusion impairs mitochondrial O2 uptake, preconditioning prevents this lesion and enhances ATP resynthesis. In lieu of norepinephrine release induced by transient shock, preconditioning may be achieved by brief infusion of exogenous norepinephrine. Stimulating the ae1 adrenergic pathway distally would allow preconditioning without the increased end-organ O2 demand or elevated vascular resistance induced by norepinephrine. Therefore, the aims of this proposal are to: 1. Characterize the preconditioning effect of transient shock (transient ischemia, TI) on recovery of end organ function (isolated heart) following a subsequent ischemia- reperfusion insult. 2. Investigate the role of the sympathetic neurotransmitter, norepinephrine (NE), in mediating preconditioning induced by transient ischemia. 3. Investigate the role of the adrenergic pathways in transducing preconditioning induced by NE. 4. Investigate the role of the ischemic metabolite, adenosine, in mediating preconditioning induced by TI or ae1 pathway. 5. Characterize the upregulation of energy metabolism as the basis of preconditioning.