The response of the myocardium to prolonged or chronic ischemia may differ from the well documented changes that occur acutely subsequent to the onset of hypoperfusion. Therefore, we have examined in an instrumented canine model and using spatially localized spectroscopy to achieve transmural differentiation, the myocardial HEP and Pi levels as well as wall thickening in situ during prolonged ischemia induced by sustained coronary artery stenosis. The results demonstrate that subtotal coronary artery occlusion causes immediate and transmurally inhomogeneous decreases in the myocardial HEP content and increase in the Pi /CP ratio; however, during prolonged mild hypoperfusion, metabolic changes occur which lead to statistically significant recovery of CP (but not ATP) and disappearance of Pi despite the persistence of reduced blood flow and oxygen supply. Upon release of the occlusion, the previously ischemic muscle recovered blood flow, and some (but not all) of its preischemic contractile function without parallel changes in the HEP levels. It is concluded that normal HEP and Pi levels cannot be equated with either the absence of underperfusion or insensitivity of NMR spectroscopy to ischemia. Rather, it is imperative that both functional and spectroscopic measurements are performed simultaneously to distinguish between ischemic myocardium which is adapted versus unadapted to the hypoperfusion.