SSR69071, an elastase inhibitor, reduces myocardial infarct size following ischemia-reperfusion injury.
Neutrophil elastase contributes to the severity of cardiac damage following coronary ischemia and reperfusion. We evaluated the effects of 2-(9-(2-piperidinoethoxy)-4-oxo-4H-pyridol[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methyethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide hemihydrate (SSR69071), a novel, potent and selective inhibitor of neutrophil elastase, on infarct size in anaesthetized rabbits subjected to coronary artery occlusion for 30 min followed by reperfusion for 120 min. SSR69071 (3 mg/kg i.v.) reduced cardiac infarct size when administered before ischemia (-39%, P<0.05) or just prior to reperfusion (-37%, P<0.05). Subsequent experiments using the latter administration protocol confirmed the ability of SSR69071 (1 and 3 mg/kg i.v.) to reduce infarct size. This cardioprotective activity was associated with inhibition of cardiac elastase.
Bidouard
Jean-Pierre
JP
Cardiovascular-Thrombosis Department, Sanofi-Synthelabo Research, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, France.
Duval
Nicole
N
Kapui
Zoltan
Z
Herbert
Jean-Marc
JM
O'Connor
Stephen E
SE
Janiak
Philip
P
D000818:Animals; D003499:Cyclic S-Oxides / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy*; D011817:Rabbits; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*
D003499:Cyclic S-Oxides; C474251:SSR 69071; D013844:Thiazoles; D019272:Leukocyte Elastase