Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance

Preconditioning to ischemic tolerance is a phenomenon in which brief episod es of a subtoxic insult induce a robust protection against the deleterious effects of subsequent, prolonged, lethal ischemia. The subtoxic stimuli tha t constitute the preconditioning event are quite diverse, ranging from brie f ischemic episodes, spreading depression or potassium depolarization, chem ical inhibition of oxidative phosphorylation, exposure to excitotoxins and cytokines. The beneficial effects of preconditioning were first demonstrate d in the heart; it is now clear that preconditioning can induce ischemic to lerance in a variety of organ systems including brain, heart, liver, small intestine, skeletal muscle, kidney, and lung. There are two temporally and mechanistically distinct types of protection afforded by preconditioning st imuli, acute and delayed preconditioning. The signaling cascades that initi ate the acute and delayed preconditioning responses may have similar bioche mical components. However, the protective effects of acute preconditioning are protein synthesis-independent, mediated by post-translational protein m odifications, and are short-lived. The effects of delayed preconditioning r equire new protein synthesis and are sustained for days to weeks. Elucidati on of the molecular mechanisms that are involved in preconditioning and isc hemic tolerance and identification of drugs that mimic this protective resp onse have the potential to improve the prognosis of patients at risk for is chemic injury. This article focuses on recent findings on the effects of is chemic preconditioning in the cardiac and nervous systems and discusses pot ential targets for a successful therapeutic approach to limit ischemia-repe rfusion injury.