Although in experimental hypertension the cardioprotective effects of ischemic preconditioning (PC) appear to be maintained, most studies have examined the short-term hypertension in juvenile animals. However, aging may be an additional factor that influences the effectiveness of PC. The aim of this study was to characterise the effects on PC of LVH and aging simultaneously. Hearts from spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) were studied. Excised hearts were Langendorff-perfused to give equivalent coronary flow per gram heart weight. The left main coronary artery was occluded for 35 min followed by 120 min reperfusion. Infarct size was determined by tetrazolium staining. Heart size was assessed as left ventricle/body weight ratio (LV/BW). PC was effected with 2 x 5 min periods of global ischemia prior to coronary occlusion. Hearts were studied at 3-4 months (juvenile), 7-8 months (mature) or 12-13 months (aging). LV/BW ratio in SHR increased relative to WKY controls by 20%, 32% and 40% in juvenile, mature and aging hearts, respectively, but ischemic risk zone size was similar in all groups (52-59% of LV). PC was equally effective at limiting infarct size in juvenile and mature SHR and WKY hearts but was ineffective in aging hearts from both WKY and SHR. Since angiotensin-converting enzyme inhibitors enhance sub-threshold PC in normal myocardium, we also examined the action of captopril (Cap) in aging hearts. Additional aging hearts received treatment with Cap 200 microM as an adjunct to PC. Although Cap+PC was able to induce modest protection in aging WKY hearts, this was not seen in aging SHR hearts. We conclude that PC is lost in longstanding hypertension through independent contributions of both hypertension and aging. These findings may have implications for the clinical development of preconditioning-based therapies since elderly patients with longstanding hypertension are at high risk of developing ischemic heart disease.