Lvdp

Time

Precornftionirig

Zwo-flow. global ischemia

Raperfuson

Figure 25. Left vcnricular developed pressure recordings from isolated rat hearts perfused with Krebs-Henseleit in Langelldoiff mode (LVDP is defined as the difference between systolic and diastolic let! ventricular pressure). After stabilization, zero-flow global ischemia was induced by clamping the supply of the preheated perfusate to the heart followed by reperfusiou. A. Note the high diastolic pressure (black arrow) and the low LVDP at roperfusion. B The same protocol of ischemia and reperfusion was applied to a heart that had been subjected to four brief episodes of ischemia-reperfusion (preconditioning). Note the acceleration of ischemic contracture (white arrow), the lower diastolic pressure (black arrow) and the higher LVDP, indicating improved functional recovery (data from our laboratory).

Normal

Inducible HSP7Û protein expression Heat Norma) Heat Normal

Heat

Figure 26. Western blots. Heat induces Hsp7{) protein expression in ral myocardium (A). Heat reduces the phosphorylation of p54 and p46 .INK in rat heart subjected to zero-flow global ischemia and reperfusion (B). This is probably the ciTect of a negative interaction between Hsp70 and JiNKs (modified by Pantos152). "Norma]" stands for normal hearts and "Heat" stands for hearts subjected to heat stress.

Figure 26. Western blots. Heat induces Hsp7{) protein expression in ral myocardium (A). Heat reduces the phosphorylation of p54 and p46 .INK in rat heart subjected to zero-flow global ischemia and reperfusion (B). This is probably the ciTect of a negative interaction between Hsp70 and JiNKs (modified by Pantos152). "Norma]" stands for normal hearts and "Heat" stands for hearts subjected to heat stress.

preconditioning). Ischemic preconditioning limits infarct size, reduces reperfusion arrhythmias (not in pigs) and improves recovery of function in various experimental models. Figure 25. During the preconditioning episodes, intracellular triggering of the response may be due to the release of adenosine, bradykinin, opioids, prostacycline, nitric oxide, reactive oxygen species or TNF-a. The trigger substances also cause activation of kinase cascades either through G-protein coupled membrane receptors or directly. Protein kinase C, tyrosine kinase, as well as mitogen activated protein kinase families, are important mediators in different experimental models. The mitochondrial ATP dependent potassium channel has been implicated as a trigger or mediator, or even as end-effector, of the immediate cardioprotective effect. The early triggering response leads to the transcription of cardioprotective mediators, such iNOS, COX-2, antioxidant enzymes and heat shock proteins and their expression coincides with the late preconditioning effect, reviewed by Schulz193 and Valen.194 Ischemic preconditioning provides an important paradigm to unravel the cellular defense mechanisms against ischemic stress, (for a detailed description see chapter 3).

3.2 Heat stress induced 'cross tolerance' to myocardial ischemia

The phenomenon of ischemic preconditioning is mimicked by multiple environmental stresses. Prominent among them are heat stress and hypoxia. Transient hyperthermia is shown to induce delayed myocardial protection against reperfusion injury by preserving ventricular function, preventing arrhythmias and reducing myocardial necrosis. NO or ROS release by a sublethal hyperthermic stress triggers a complex cascade of signaling events that include activation of protein kinase C, and mitogen-activated protein kinases (MAPK) that ultimately lead to the expression of important cardioprotective proteins, such as the inducible nitric oxide synthase, cyclooxygenase-2, antioxidant enzymes and heat shock proteins.195 Furthermore, in heat stress treated perfused hearts, ischemia and reperfusion induced activation of the pro-apoptotic JNKs is shown to be decreased due to its negative regulation by Hsp70.152 Figure 26.

3.3 Chronic hypoxia

Clinical-epidemiological observations point out that the incidence of myocardial infarction is less in people living at high altitude, suggesting that hypoxia corresponds to a phenotype of increased ischemic tolerance. Subsequent experiments demonstrated that hearts exposed to chronic hypoxia are more tolerant to ischemic stress. In fact, coronary artery occlusion followed by reperfusion resulted in smaller infarctions in rats exposed to hypobaric hypoxia of 7000m for 8h/day, 5 days a week. This response was associated with overexpression of active PKC8 and the infarct size-limiting effect induced by chronic hypoxia was abolished by rottlerin, a specific inhibitor of PKC8 activation. KATp channels, ROS, NO, opioids and erythropoietin have also been implicated in the cardioprotection induced by chronic hypoxia.196,197 Furthermore, in animals with systemic hypoxia, downregulation of PPAR-a and PPAR-a regulated genes is observed198 and this is accompanied by an isoform switch from a-MHC to P-MHC.199

Concluding remarks

Ischemic preconditioning is the phenomenon characterized by increased myocardial tolerance to ischemia and reperfusion injury induced by prior brief episodes of ischemia and reperfusion. There is an early phase lasting hours and a late phase lasting 1 to 3 days. The mechanisms of this phenomenon are not fully understood. It seems that substances released during the brief episodes of ischemia and reperfusion trigger a sequence of intracellular cascades and protective events. The phenomenon of ischemic preconditioning is mimicked by multiple environmental stresses. Prominent among them are heat stress and hypoxia.

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