Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits

Myocardial ischemia-reperfusion injury can be related to complement activat ion with generation of chemotactic agents, adhesion molecule expression, re lease of cytokines and oxygen-derived free radicals, and subsequent neutrop hil accumulation. In the present study the cardioprotective effects of a no vel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial Ischemia (1) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC ly sis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH- 248 (1 mg/kg body weight) administered 5 min before reperfusion significant ly attenuated myocardial injury (31.9 +/- 2.5 vs 8.9 +/- 1.6% necrosis/area at risk; p < 0.01). The cardioprotective effect was dose dependent. The re duction of myocardial injury was also observed as diminished plasma creatin e kinase activity in C1s-INH-248-treated animals (70.7 +/- 6.8 vs 45.1 +/- 3.9 U/g protein after 3 h of reperfusion,p < 0.05). Further, cardiac myelop eroxidase activity (i.e., a marker of PMN accumulation) in the ischemic and necrotic area was significantly reduced following C1s-INH-248 treatment (1 .31 +/- 0.23 vs 0.4 +/- 0.05 U/100 mg tissue in necrotic area, p < 0.01). T hus, blocking the classical complement pathway with a highly specific and p otent synthetic inhibitor of the activated C1 complex appears to bean effec tive mean to preserve Ischemic myocardium from injury following reperfusion .