NEUTROPHIL ELASTASE INHIBITOR ICI-200,880 PROTECTS AGAINST ATTENUATION OF CORONARY FLOW RESERVE AND MYOCARDIAL DYSFUNCTION FOLLOWING TEMPORARY CORONARY-ARTERY OCCLUSION IN THE DOG

Objective: Diminished coronary flow reserve and myocardial dysfunction following coronary artery occlusion and reperfusion have been attribu ted to neutrophil infiltration into the reperfused regions. Release of free radicals and elastase during reperfusion may also contribute to ischaemia-reperfusion induced changes. The aim of this study was to de termine the effect of an elastase inhibitor on reperfusion induced att enuated coronary flow reserve and myocardial dysfunction. Methods: Ana esthetised dogs were subjected to 1 h of left anterior descending coro nary artery occlusion and 2 h of reperfusion. Ten minutes before reper fusion, dogs were randomly given saline or the neutrophil elastase inh ibitor ICI 200,880 (10 mg.kg(-1)) and treatment was continued for the next 70 min. While the regional myocardial shortening fraction and cor onary blood flow responses to acetylcholine and glyceryl trinitrate we re attenuated following coronary reperfusion in saline treated dogs, s imilar reductions were not observed in the ICI 200,880 treated dogs (p < 0.01). Histopathology showed myocardial injury and extensive neutro phil infiltration in the reperfused regions in saline treated animals. In contrast, neutrophil infiltration was minimal in the ICI 200,880 t reated dogs, in spite of myocardial injury. Myeloperoxidase, an index of neutraphil infiltration, was increased (p < 0.02 v control regions) in the reperfused regions in saline treated dogs, but not in the ICI 200,880 treated dogs. Flow cytometry also showed diminished neutrophil infiltration and oxidative burst in reperfused myocardium of ICI 200, 880 treated (v saline treated) dogs. Conclusions: The elastase inhibit or ICI 200,880 protects against ischaemia-reperfusion induced attenuat ed coronary flow reserve and myocardial dysfunction, and this protecti ve effect is associated with decreased neutrophil infiltration into th e reperfused regions.