β-Adrenergic signaling and ROS: Pivotal roles in intermittent, normobaric hypoxia-induced cardioprotection

Intermittent, normobaric hypoxia conditioning of dogs evokes robust myocardial resistance against ischemia-reperfusion injury, but the mechanisms responsible for this powerful cardioprotection are undefined. Specifically, a 20 day program of multiple, brief bouts of normobaric, moderate hypoxia affords striking cardioprotection against myocardial infarction and ventricular arrhythmias resulting from subsequent coronary artery occlusion and reperfusion. Recent work by the authors has examined the roles of -adrenergic signaling and reactive oxygen and nitrogen metabolites in the progressive development of this cardioprotection. These studies demonstrate that oral administration of a 1-adrenoceptor antagonist, metoprolol, or sulfhydryl antioxidant N-acetylcysteine during the intermittent hypoxia conditioning program abrogates the cardioprotection. The hypoxia program lowered myocardial nitric oxide synthase (NOS) activity and contents of NOS isoforms, which could dampen harmful formation of oxyradicals and peroxynitrite upon reperfusion of occluded coronary arteries. This chapter discusses this work and places it in the context of research by other investigators attempting to delineate the mechanisms of this powerful, clinically relevant cardioprotective phenomenon.