Triggers and promoters of ischaemic preconditioning.

See article by Wang et al. [10] (pages 33 –42) in this tioning through nitric oxide (NO), which is generated by issue. activation of endothelial derived constitutive nitric oxide Ischaemia / reperfusion injury in coronary artery disease synthase enzyme (cNOS). Since Furchgott [7], in 1986 patients confers increased morbidity and mortality due to identified NO as the endothelial derived relaxing factor, it pump dysfunction and arrhythmia. In cardiac patients, has been implicated in numerous cardiovascular diseases, ischaemic episodes still occur in an unpredictable manner atherosclerosis, hypertension and cardiomyopathy. Aside despite multiple drug therapies and revascularization strafrom the disease process, it has also been described to have tegies. Therefore, unrelenting efforts in the way of iskey roles in normal homeostasis and protection against chaemic preconditioning have been underway to devise cellular injury [8]. Thus the seminal role of NO in treatment modalities for preparing the heart to face isischaemic preconditioning remains an active area of rechaemia in a more benign (ischemia can never be benign) search. manner. Lipopolysaccharides (LPS) have been shown by Brown Ischaemic preconditioning describes the process of et al. to be a trigger in the late preconditioning process [9]. increasing myocardial tolerance to ischaemia / reperfusion Monophosphoryl lipid A (MLA), a modified nontoxic (I /R) injury by providing sub lethal episodes of ischaemia / endotoxin, is a powerful trigger for the production of reperfusion. Murray et al. described the preconditioning inducible NO synthase (iNOS). This theory has led to process in 1986 [1]. They have shown that brief, intermitrecent experimentations and hypotheses that late preconditent bouts of ischaemia followed by reperfusion had a tioning may be mediated via the NO pathway, although the protective effect on canine myocardial tissue against a exact molecular chain of events is unknown. subsequent ischaemic insult of prolonged duration. When In this issue of Cardiovascular Research, Wang et al. these preconditioned animals were subjected to a 40-min [10] have hypothesized that LPS triggers the late precondiocclusion of left circumflex artery, the ensuing myocardial tioning process against myocardial infarction via iNOS necrosis was only 25% of those hearts not previously gene expression. The investigators, using a rat model of subjected to preconditioning. The process of preconditionmyocardial ischaemia / reperfusion, showed that LPS proing has two phases, the early preconditioning phase, which occurs in the first 3 h and the late phase, which occurs Table 1 between 12 to 72 h [2] after the ischaemic insult. Several Mediators of preconditioning proposed mechanisms for the preconditioning response Mediator Mechanism initially included: (1) decreased tissue accumulation of Adenosine – Through adenosine A, receptor activation breakdown products of glycogen and adenine nucleotides mediates PKC and tyrosine kinase 1 such as lactate, H , inorganic phosphate and NH , (2) 3 Acetylcholine – Protein kinase activation activation or synthesis of enzyme systems to protect Opioids i.e. morphine – Activation of S, -opioid receptor (G i /o protein-mediated) [12] myocardium from ischaemic injury. Norepinephrine – a-adrenergic receptor mediated protein A list of triggers and mediators of the preconditioning kinase activation. process include, adenosine [3], acetylcholine [4], bradyNitric oxide – Activation of ATP-sensitive potassium kinin [5], and lipopolysaccharides [6] (Tables 1 and 2). It channels. is hypothesized that these three agents mediate precondiSerotonin – Unknown Cytokines, 1L1, 1L2 – Induce iNOS protein expression [13]. TNF a, Interferon *Corresponding author. Tel.: 11-573-882-2640; fax: 11-573-884Reactive oxygen species – Induce iNOS protein expression [13]. 7743.