Pharmacological Ischaemic Preconditioning: Design and Synthesis of mito-KATP Channel Openers and Aldose Reductase Inhibitors

The ischaemic preconditioning (IPC) is a biological phenomenon in which brief period of coronary occlusion trigger a “self-defence” mechanism which reduces the injury determined by a subsequent and more prolonged ischaemia and gives myocardiocytes an increased resistance against ischaemia-induced cell damage, resulting in a marked reduction of the infarct size. This phenomenon, not yet completely clarified, is triggered by several processes, both receptor-mediated (bradykinin, adenosine) and receptor-indipendent (involving NO and reactive oxygen species). Recent experimental data have indicated the endogenous activation of mito-KATP as one of the main effector in anti-ischaemic cardiac protection. Some authors have also hypothesized that functional recovery after ischaemia is predicated on the ability of the myocyte to maintain sufficient substrate metabolism during ischaemia. This hypothesis starts from the observation that glucose metabolism via the polyol pathway, and consequently aldose reductase (AR) activity, is increased in ischemic hearts and recently, it was demonstrated that inhibition of AR protects rat hearts from ischemic injury and improves functional recovery upon reperfusion. Both mito-KATP openers (mito-KCOs) and aldose reductase inhibitors (ARIs) could have a fundamental role in the treatment of the myocardial ischaemia, in particular, the former may afford a “chemical preconditioning” that confers on the heart the ability to better withstand the oxygen deprivation and, consequently, to suffer less tissue damage during acute myocardial infarction; the latter as a potential therapeutic adjuncts in treating acute myocardial ischaemia and evolving infarction.