AJP - Heart and Circulatory Physiology, Vol 271, Issue 5 1947-H1952, Copyright © 1996 by American Physiological Society

ARTICLES

Protease inhibition attenuates microvascular dysfunction in postischemic skeletal muscle

D. L. Carden and R. J. Korthuis
Department of Physiology and Biophysics, Louisiana State University Medical Center, School of Medicine, Shreveport 71130, USA.

Neutrophils accumulate in skeletal muscle subjected to ischemia-reperfusion 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 ischemia-reperfusion-induced granulocyte accumulation and microvascular dysfunction in skeletal muscle. We examined the effect of three structurally unrelated elastase inhibitors [eglin C, MeOsuc-Ala-Ala-Val-CH2Cl (MAAPV), or L-658758], administered at the onset of reperfusion, on neutrophil content and the increase in microvascular permeability induced by 4 h of ischemia and 0.5 h of reperfusion in the isolated canine gracilis muscle. Changes in vascular permeability (1 - sigma) were assessed by determining the solvent drag reflection coefficient for total plasma proteins (sigma) in the following groups: 1) 4.5 h of continuous perfusion (nonischemic), 2) ischemia-reperfusion alone, 3) ischemia-reperfusion + eglin C, 4) ischemia-reperfusion + MAAPV, and 5) ischemia-reperfusion + L-658758. Muscle neutrophil content was monitored by assessing tissue myeloperoxidase (MPO) activity in biopsies obtained at the end of the experiments. In nonischemic muscles, 1 - sigma and MPO activity averaged 0.13 +/- 0.03 and 0.7 +/- 0.2 units/g wet wt, respectively. Ischemia-reperfusion was associated with marked increases in microvascular permeability (1 - sigma = 0.39 +/- 0.02) and muscle MPO activity (8.9 +/- 1.2 units/g wet wt) that were attenuated by eglin C, MAAPV, and L-658758 (1 - sigma = 0.21 +/- 0.01, 0.22 +/- 0.02, and 0.21 +/- 0.03, respectively; MPO activity = 2.7 +/- 0.4, 2.1 +/- 0.8, and 2.8 +/- 1.8 units/g wet wt, 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.

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