The frequency of chronic hypertension among cardiac surgery patients implies that experimental therapies that protect normotensive myocardium will be more clinically relevant if they also protect chronically hypertensive myocardium. We tested the effectiveness of three experimental therapies that protect normotensive myocardium from ischemic injury in both normotensive (NTR) and spontaneously hypertensive (SHR) isolated Sprague-Dawley rat hearts. Post-ischemic recovery of ATP, left ventricular end diastolic pressure, developed pressure, negative and positive left ventricular dP/dt (-dP/dt and +dP/dt) and coronary flow (CF) were compared in ischemically preconditioned, adenosine-pretreated, bethanechol-pretreated and untreated NTR and SHR isolated rat hearts. The effect of time on our preparation was evaluated by comparison to NTR and SHR hearts maintained in vitro for equal duration but not subjected to an ischemic insult (N = 7, all groups). Preconditioning, adenosine and bethanechol significantly improved recovery of ATP, left ventricular end diastolic pressure, developed pressure, -dP/dt, +dP/dt and coronary flow in both NTR and SHR hearts (P < 0.001 vs. untreated, all comparisons). Although recovery was not so pronounced in SHR hearts, these results suggest that experimental therapies that protect normotensive myocardium also protect chronically hypertensive myocardium. The effect of adenosine and that of ischemic preconditioning were nearly identical, and both treatments were significantly more cardioprotective than bethanechol in both NTR and SHR hearts (P < .05 and P < .001, respectively). This result suggests that adenosine buildup is more important than muscarinic receptor stimulation as a mechanism of the protection afforded by ischemic preconditioning.