Protease inhibition attenuates granulocyte accumulation and microvascular dysfunction in postischemic skeletal muscle. Carden, Donna L., and Ronald J. Korthuis. Departments of Physiology and Biophysics and Medicine, Louisiana State University Medical Center, School of Medicine in Shreveport, Shreveport, LA 71130
APStracts 3:0182H, 1996.
Neutrophils accumulate in skeletal muscle subjected to ischemia/reperfusion (I/R) and appear to contribute to reperfusion -induced microvascular dysfunction. The overall objective of this study was to assess the role of the neutrophilic hydrolytic enzyme, elastase, in I/R-induced granulocyte accumulation and microvascular dysfunction in skeletal muscle. We examined the effect of three structurally unrelated elastase inhibitors (Eglin C, MAAPV or L658,758), administered at the onset of reperfusion, on neutrophil content and the increase in microvascular permeability induced by 4 hr of ischemia and 0.5 hr of reperfusion in the isolated canine gracilis muscle. Changes in vascular permeability (1-s) were assessed by determining the solvent drag reflection coefficient for total plasma proteins (s) in the following groups: 1) 4.5 hr continuous perfusion (non-ischemic); 2) I/R alone; 3) I/R+Elgin C; 4) I/R+MAAPV; and 5) I/R+L658,758. Muscle neutrophil content was monitored by assessing tissue myeloperoxidase (MPO) activity in biopsies obtained at the end of the experiments. In non-ischemic muscles, 1-s and MPO averaged 0.13+0.03 and 0.7 +/- 0.2 units/gram wet weight, respectively. I/R was associated with marked increases in microvascular permeability (1-s = 0.39+0.02) and muscle MPO (8.9+1.2 units/gram wet weight) that were attenuated by Eglin C, MAAPV and L658,758 (1-s = 0.21+0.01, 0.22+0.02, 0.21+0.03, respectively; MPO=2.7+0.4, 2.1+0.8, and 2.8+1.8 units/gram wet weight; respectively). These results suggest that granulocyte accumulation in postischemic skeletal muscle is dependent on the release of elastase from activated phagocytic cells. Moreover, neutrophilic elastase appears to play a major role in reperfusion-induced increases in microvascular permeability in skeletal muscle. 

Received 11 January 1996; accepted in final form 18 April 1996.
APS Manuscript Number H14-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 8 May 96