Compared with normal hearts, those with pathology (hypertrophy) are less tolerant of metabolic stresses such as ischemia. Pharmacologic intervention administered prior to such stress could provide significant protection. This study determined, firstly, whether the pentose sugar ribose, previously shown to improve postischemic recovery of energy stores and function, protects against ischemia when administered as a pretreatment. Secondly, the efficacy of this same pretreatment protocol was determined in hearts with pathology (hypertrophy). For study 1, Sprague-Dawley rats received equal volumes of either vehicle (bolus i.v. saline) or ribose (100 mg/kg) before global myocardial ischemia. In study 2, spontaneously hypertensive rats (SHR; blood pressure approximately 200/130) with myocardial hypertrophy underwent the same treatment protocol and assessments. In vivo left ventricular function was measured and myocardial metabolites and tolerance to ischemia were assessed. In normal hearts, ribose pretreatment significantly elevated the heart's energy stores (glycogen), and delayed the onset of irreversible ischemic injury by 25%. However, in vivo ventricular relaxation was reduced by 41% in the ribose group. In SHR, ribose pretreatment did not produce significant elevations in the heart's energy or improvements in tolerance to global ischemia, but significantly improved ventricular function (maximal rate of pressure rise (+dP/dt(max)), 25%; normalized contractility ((+dP/dt)/P), 13%) despite no change in hemodynamics. Thus, administration of ribose in advance of global myocardial ischemia does provide metabolic benefit in normal hearts. However, in hypertrophied hearts, ribose did not affect ischemic tolerance but improved ventricular function.