The purpose of this study was to evaluate the ability of novel semiselective matrix metalloproteinase inhibitors (MMPI) to protect myocardial structure-function in the setting of ischemia-reperfusion injury. For this purpose, an isolated rat model of myocardial stunning and infarction was used. Isolated hearts were subjected to 20-30 minutes of global no-flow ischemia and 30-minute reperfusion. Myocardial performance was assessed as the product of the heart rate and left ventricular developed pressure (rate-pressure product, RPP). Coronary flow rates, ventricular weights, indicators of muscle (troponin I), and fibrillar collagen damage (collagen opalation) were measured. Four MMPI were tested: 2 non-hydroxamate, semiselective inhibitors (PY-2 and 1,2-HOPO-2) and 2 broad-spectrum inhibitors (PD166793 and CGS27023A). The non-hydroxamate, semiselective inhibitors were shown to be nontoxic in cocultures of cardiac cells. Results indicate that semiselective inhibitors (in particular 1,2-HOPO-2) yield improved cardiac performance (~23% higher RPP vs. controls) and coronary flow rates (~22%), reducing muscle (~25%) and fibrillar collagen damage (~60%). Evidence suggests the involvement of matrix metalloproteinase-2 in these actions. Interestingly, broad-spectrum inhibitors only show modest improvement (~8% higher RPP vs. controls) without affecting the other measured parameters. In conclusion, semiselective MMPI can act as cardioprotectors in isolated perfused rat hearts. Protection is observed in all structural components of the myocardium translating into improved contractile function. Based on these findings, non-hydroxamate, semiselective MMPI warrant further studies as to their ability to protect ischemic myocardium in the in vivo setting.