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 attributed 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 determine the effect of an elastase inhibitor on reperfusion induced attenuated coronary flow reserve and myocardial dysfunction.


METHODS
Anaesthetised dogs were subjected to 1 h of left anterior descending coronary artery occlusion and 2 h of reperfusion. Ten minutes before reperfusion, dogs were randomly given saline or the neutrophil elastase inhibitor ICI 200,880 (10 mg.kg-1) and treatment was continued for the next 70 min. While the regional myocardial shortening fraction and coronary blood flow responses to acetylcholine and glyceryl trinitrate were attenuated following coronary reperfusion in saline treated dogs, similar reductions were not observed in the ICI 200,880 treated dogs (p < 0.01). Histopathology showed myocardial injury and extensive neutrophil infiltration in the reperfused regions in saline treated animals. In contrast, neutrophil infiltration was minimal in the ICI 200,880 treated dogs, in spite of myocardial injury. Myeloperoxidase, an index of neutrophil 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 inhibitor ICI 200,880 protects against ischaemia-reperfusion induced attenuated coronary flow reserve and myocardial dysfunction, and this protective effect is associated with decreased neutrophil infiltration into the reperfused regions.
University of Florida College of Medicine, Gainesville 32610-0277.
J L
JL
Mehta
W W
WW
Nichols
F A
FA
Nicolini
J
J
Hendricks
W H
WH
Donnelly
T G
TG
Saldeen
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003250:Constriction; D003326:Coronary Circulation / Q000502:physiology*; D003331:Coronary Vessels; D004195:Disease Models, Animal; D004285:Dogs; D019272:Leukocyte Elastase; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D005996:Nitroglycerin / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011897:Random Allocation; D012039:Regional Blood Flow / Q000187:drug effects
D009842:Oligopeptides; C069695:ICI 200880; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D005996:Nitroglycerin; D000109:Acetylcholine