Calcium-activated neutral protease inhibitor(E-64c) and reperfusion for experimental myocardial infarction.

Abstract

We examined the efficacy of the combination of coronary reperfusion Address for reprints:

Attenuation of neutrophil-mediated myocardial ischemia-reperfusion injury by a calpain inhibitor

“…Increased calpain activity has been reported in the setting of myocardial ischemia (hypoxia) and/or reperfusion (10,14,23,31,33,40,41) and seems to have a critical role in breakdown of myocardial proteins resulting in tissue damage (26,35). Furthermore, the cardioprotective effects of calpain inhibitors have been reported after ischemia (11,22,33,34,39,40). However, the cardioprotective effects of a calpain inhibitor shown in the present study are significantly different from those of other studies because the postischemic cardiac dysfunction is induced by perfusion of PMNs.…”

“…Increased calpain activity has been reported in the setting of myocardial ischemia (hypoxia) and/or reperfusion (10,14,23,31,33,40,41) and seems to have a critical role in breakdown of myocardial proteins resulting in tissue damage (26,35). Furthermore, the cardioprotective effects of calpain inhibitors have been reported after ischemia (11,22,33,34,39,40).…”

“…There are two major isoforms of calpain, calpain I (or -calpain) and calpain II (or m-calpain), which require micromolar and millimolar concentrations, respectively, of intracellular calcium for activation (1). Inhibition of calpain activity has been shown to reduce organ injury associated with ischemia-reperfusion (I/R) of the brain (21, 37), liver (12, 13) and heart (11,22,33,34,39,40). Furthermore, recent in vivo and in vitro studies have shown that calpain inhibitors attenuate the surface expression of P-selectin on endothelial cells (2) and prevent the nuclear translocation of the transcription factor nuclear factor-B (44), which is important for expression of a variety of cell adhesion molecules on the endothelium.…”

Activity profile of calpains I and II in chronically infarcted rat myocardium – influence of the calpain inhibitor CAL 9961

“…The results in Figure 5a,b indicate a higher selectivity of CAL 9961 to calpain II. Whereas some studies showed that several calpain inhibitors such as E-64, CI-1 and NCO-700 inhibit the activity of the calpains in the ischaemicreperfused rat heart (Yoshida et al, 1995b;Toda et al, 1989;Cuzzocrea et al, 2000;Toyo-Oka et al, 1982), the present study has demonstrated for the ®rst time the inhibitory action of the calpain inhibitor, CAL 9961, on the activity of the calpains in an animal model of permanent coronary occlusion in rats. Earlier studies demonstrated a contribution of activated calpains I and II in the proteolytic digestion of microtubules (Billger et al, 1988;Sato et al, 1993), actinbinding protein (Wencel-Drake et al, 1991), fodrin (Yoshida et al, 1995a) and vinculin (Steenbergen et al, 1987a) in the ischaemic myocardium which was associated with subsequent myocyte death and loss of myocardial structural integrity and, eventually, cardiac dysfunction.…”

Reduction of myocardial infarction by calpain inhibitors A-705239 and A-705253 in isolated perfused rabbit hearts

“…Calpain inhibitors were also found to be protective in prolonged hypothermic cardiac preservation (Saito et al, 1999) and against virus-induced apoptotic myocardial injury (DeBiasi et al, 2001). So far, only a few studies are available regarding the effect of calpain inhibition in experimental models of myocardial infarction, in which the infarct size could be reduced by pretreatment with the calcium-activated neutral protease inhibitor E-64c in dogs (Toda et al, 1989) or with calpain inhibitor-I in isolated perfused rat hearts (Iwamoto et al, 1999;Perrin et al, 2003). Therefore, in the present study we have evaluated the cardioprotective properties of two newly developed calpain inhibitors in isolated perfused rabbit hearts following temporary coronary occlusion.…”