NOS and cardiac ischemic preconditioning

Protecting the heart from these harmful consequences of coronary occlusion has been the goal of ongoing research by a number of investigators for many decades. In recent years, cardiac ischemic preconditioning (i.e., the brief sequences of coronary occlusion and reperfusion before prolonged occlusion) has been extensively studied and found to be cardioprotective against ischemia/reperfusion (I/R) injury. Its various roles in cardioprotection involve many factors, including the nitric oxide signaling pathways. Ischaemic preconditioning (IPC) refers to processes by which brief, sublethal episodes of ischemia stimulate a protective response against subsequent, more severe, ischemia. IPC has been described in many tissues, including the heart, brain, liver, and gastrointestinal tract. Although there are similarities between different tissues, it is not known whether the triggers and mediators of IPC are the same in all tissues. The potential protective mechanisms include alterations in cell death genes, heat shock proteins, lipid peroxidation, inflammation, and mitochondrial metabolism. IPC has been divided into rapid and delayed forms. Rapid IPC occurs when the preconditioning stimulus precedes the severe ischemic insult by a short time interval (minutes to several hours), while delayed IPC occurs requires a longer time interval (hours to days) to develop. Furthermore ischemic preconditioning (IPC) is the induction of a brief episode of ischemia and reperfusion in myocardium to markedly reduce tissue damage induced by prolonged ischemia. Ischemic preconditioning as a potent cardioprotective method against I/R injury was first reported by Murry et al. in 1986. In their study using dogs, four sequential episodes of 5-minute occlusion each followed by 5-minute reperfusion were induced in the left circumflex coronary artery, preceding a sustained 40-minute prolonged occlusion period. Although many investigations have documented preconditioning as an intervention capable of protecting the heart against I/R injury, the cardioprotective effect of IPC is relatively short-lived and the underlying mechanism is not completely understood. More recently it was found that the fundamental processes and the end-target of cardioprotection of IPC mechanisms are related to the prevention of mitochondrial permeability transition (MPT). It was shown that IPC was not involved in the coronary blood flow through the damaged area, however, in 1991 Liu et al. discovered that stimulation of cardiac Gi-coupled adenosine receptor type 1 (A1) was necessary for the preconditioning effect. A study showed that IPC’s protection could be attenuated by an adenosine receptor antagonist, whereas the infusion of adenosine, or the A1-specific agonist N6-1-(phenyl-2R-isopropyl) adenosine (R-PIA), could reduce the infarct size. Therefore, cardioprotection of IPC was achieved as ischemic myocardium rapidly degraded ATP to adenosine, which then accumulated in this area. Furthermore bradykinin and opioid receptors are also involved in the IPC process. During the preconditioning ischemia, bradykinin and endogenous opioid are released from the heart, together with the production of adenosine as a result of metabolic breakdown of ATP. These 3 ligands activate their respective G-protein coupled receptors (GPCRs), which work on the other pathways to protect the heart from ischemic conditions. Nevertheless, the protection of IPC could not be completely blocked if 1 of these 3 receptors is inhibited. On the other hand, it was suggested that combining 2 or more of these receptors produces an incremental cardioprotective effect against I/R injury of IPC. Further research has shown that increasing the number of preconditioning cycles leads to greater resistance of the heart to I/R injury. In addition to these substances and receptors, nitric oxide (NO) has been shown to play an important role in the cardioprotective process of IPC during myocardial ischemia. Pharmacologic studies suggest separable roles for each of the NOS isoforms in cerebral IPC. In a newborn rat model of hypoxia-ischaemia, preconditioning by mild hypoxia protects against more severe hypoxia 24 h later. IPC protection is prevented by L-NA, but not the iNOS specific inhibitor 7-nitroindazole or the iNOS specific inhibitor aminoguanidine, suggesting by process of elimination, the involvement of the eNOS isoform. In another rat model, both transient cerebral ischemia and LPS could protect against later ischemia. LPS treatment was associated with increased eNOS expression, and protection was blocked by L-NAME. The anesthetics isoflurane and halothane also protect against cerebral ischaemia 24 h later. iNOS induction is required and protection is blocked by the iNOS inhibitor aminoguanidine. There are several potential mechanisms by which NO mediates IPC. First, NO may be required as a trigger to stimulate downstream steps involved in the mechanisms of IPC. Second, NO may be involved as a mediator of protection by affecting neuronal resistance to ischemic phenomena. NO interacts with at least two signaling pathways important to neuronal survival: the Ras/Raf/MEK/ERK cascade, and the PI₃ kinase/Akt pathway. These pathways may be unifying mechanisms that underlie protection. Third, as a vasodilator, NO may augment blood flow by vasodilation, reducing leukocyte-endothelial interactions and platelet-endothelial interactions. Together these effects would limit the functional effect of ischemia.