1. Myocardial injury caused by ischaemia and reperfusion comes from multiple pathogenic events, including endothelial damage, neutrophil extravasation into tissue, mast cell activation, and peroxidation of
cell membrane lipids. These events are followed by myocardial cell alterations resulting eventually in cell
necrosis. An enhanced formation of
reactive oxygen species is widely accepted as a stimulus for tissue destruction and
cardiac failure. 2. In this study, we have investigated the cardioprotective effects of
M40403 in myocardial ischaemia-
reperfusion injury.
M40403 is a low molecular weight, synthetic
manganese containing
superoxide dismutase mimetic (SODm) that selectively removes
superoxide anion. Ischaemia was induced in rat hearts in vivo by ligating the left anterior descending coronary artery. Thirty minutes after the induction of ischaemia, the
ligature was removed and reperfusion allowed to occur for at least 60 min.
M40403 (0.1-1 mg kg(-1)) was given intravenously 15 min before ischaemia. 3. The results obtained in this study showed that
M40403 significantly reduced the extent of myocardial damage, mast cell degranulation and the incidence of ventricular arrhythmias. Furthermore,
M40403 significantly attenuated, in a dose-dependent manner, neutrophil infiltration in the myocardium as well as the associated induction of lipid peroxidation.
Calcium overload seen post-reperfusion of the ischaemic myocardium was also reduced by
M40403. 4. Immunohistochemical analysis for
nitrotyrosine revealed a positive staining in cardiac tissue taken after reperfusion: this was attenuated by
M40403. Moreover reperfused cardiac tissue sections showed positive staining for
P-selectin and for anti-
intercellular adhesion molecule (ICAM-1) in the vascular endothelial cells.
M40403 treatment markedly reduced the intensity and degree of
P-selectin and
ICAM-1 in these tissues. No staining for
nitrotyrosine,
P-selectin or
ICAM-1 was found in cardiac tissue taken at the end of the ischaemic period. 5. Overall,
M40403 treatment reduced the morphological signs of myocardial cell injury and significantly improved survival. 6. Taken together, these results clearly indicate that
M40403 treatment exerts a protective effect against ischaemia-reperfusion-induced myocardial injury, supporting a key role for
superoxide anion in
reperfusion injuries. This suggests that synthetic
enzymes of SOD such as
M40403, offer a novel therapeutic approach for the treatment of ischaemic
heart disease where
superoxide anion plays a dominant role.