Nitric Oxide and Short-Term Hibernation

Subendocardial blood flow (as a surrogate of regional oxygen consumption) and myocardial function are closely coupled during acute myocardial ischemia.1 2 Whereas severe ischemia results in the rapid onset of irreversible injury, viability in the face of moderate levels of acute ischemia can be maintained for several hours.3 A uniform finding during moderate steady-state ischemia is the fact that the myocardium is able to restore a balance between a limited blood supply and demand by exquisite coupling between local flow and metabolism. Thus, the transient increases in myocardial lactate and reductions in creatine phosphate and ATP at the onset of ischemia gradually return toward normal over a period of hours.4 5 The intrinsic mechanism by which myocytes are able to metabolically adapt and match function to a reduced level of flow and oxygen delivery has remained elusive, and the phenomenon has become known as “short-term hibernation.”3 Nitric oxide (NO) is a potential candidate for such regulation because it is capable of modulating contractile function under a variety of circumstances. It has become increasingly apparent that the biological actions of NO in the heart are quite complex. The effects on contractility vary among experimental preparations, and they are highly concentration-dependent. Part of this variability undoubtedly reflects the complex cellular distribution of nitric oxide synthase (NOS) and the partitioning of isoforms within particular subcellular compartments of the cardiac myocyte. As a result, local cardiac function can be modulated via NO originating from several sources. Coronary flow and shear stress stimulates NOS3 (or endothelial nitric oxide synthase [eNOS]), which produces NO that can diffuse from the vascular endothelium to affect cardiac myocyte function and metabolism in a paracrine fashion. On the basis of this mechanism, it is somewhat counterintuitive that NOS activity and cardiac NO production increase during ischemia. …