M40403 is a low-molecular-weight, synthetic manganese-containing biscyclohexylpyridine superoxide dismutase mimetic (SODm) that removes superoxide anions (O(2)(-)) without interfering with other reactive species known to be involved in cardiovascular alterations (e.g. nitric oxide [NO] and peroxynitrite [ONOO(-)]). As such, M40403 represents an important pharmacological tool to dissect the roles of O(2)(-) in functional and biochemical cardiovascular alterations induced by perfusion of high glucose concentrations into the heart. Perfusion of a high glucose concentration of glucose into the heart elicited important cardiovascular alterations characterized by QT interval prolongation, increase in coronary perfusion pressure (CPP), lipid peroxidation, decrease in MnSOD activity and DNA damage. All parameters of cardiovascular alteration were attenuated by M40403 (1-10 mg/l). Furthermore, perfusion of a high of glucose concentration induced a significant formation of nitrotyrosine as well as an activation of poly(adenosine diphosphate [ADP]-ribose) synthetase (PARS), as determined by immunohistochemical analysis of heart tissue. The extent of staining for nitrotyrosine and PARS was reduced by M40403. These results clearly indicate that O(2)(-) plays a critical role in the development of the functional and biochemical cardiovascular alterations induced by perfusion of a high concentration of glucose into the heart. Therefore, synthetic enzymes of SOD, such as M40403, offer a novel therapeutic approach for the management of various cardiovascular diseases where these radicals have been postulated to play a role.