Maj Vikram S. Kashyap, MD, USAF, MCa, Todd D. Reil, MDb, Wesley S

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Presentation transcript:

Acute arterial thrombosis causes endothelial dysfunction: A new paradigm for thrombolytic therapy Maj Vikram S. Kashyap, MD, USAF, MCa, Todd D. Reil, MDb, Wesley S. Moore, MDb, Thao X. Hoang, BSb, Hugh A. Gelabert, MDb, Russell E. Byrns, MSc, Louis J. Ignarro, PhDc, Julie A. Freischlag, MDb Journal of Vascular Surgery Volume 34, Issue 2, Pages 323-329 (August 2001) DOI: 10.1067/mva.2001.115004 Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 1 EDR plotted as percent relaxation of baseline, with log increases in the dose of acetylcholine (Ach ). EDR of nonthrombosed rat aortic ring samples is compared with that of aortic samples after thrombosis of different intervals. EDR is depressed in all thrombosis groups, reaching a nadir after 1 hour of thrombosis (13% ± 6%). There is some recovery of EDR after 1 hour of thrombosis, but EDR is still approximately 50% of control values. n = 7 to 9 per group. *P <.005, analysis of variance. Journal of Vascular Surgery 2001 34, 323-329DOI: (10.1067/mva.2001.115004) Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 2 Factor VIII immunohistochemistry of rat aorta. Endothelium is represented by the dark-staining monolayer of cells (white arrows ). Functional endothelium was present in normal control aortic specimens (C ) and in aortic specimens that had been subjected to thrombosis for 1 hour (1 hr ) and 3 hours (3 hr ). Original magnification, 200×. Journal of Vascular Surgery 2001 34, 323-329DOI: (10.1067/mva.2001.115004) Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 3 Sample scanning electron microscopy images from rat aortic rings. a, Luminal surface of normal rat aorta revealing confluent monolayer of endothelial cells (controls). b, Rat aortic luminal surface after 1 hour of thrombosis. Note confluent endothelium with minimal fibrin debris. c, Rat aortic luminal surface after 3 hours of thrombosis. Confluent monolayer of endothelium is still present, with some mild fibrin debris and platelets. d, Specimen in which intima has been purposefully rubbed, revealing complete endothelial denudation. e, Specimen in which endothelial denudation is present (top of image ), and vessel wall fracture reveals exposure of subendothelial matrix (bottom of image ). Images d and e are for comparison only and do not represent any of the experimental groups tested. (Bar in image a indicates 50 μm.) Journal of Vascular Surgery 2001 34, 323-329DOI: (10.1067/mva.2001.115004) Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 4 Local NOx levels significantly decrease after 1 hour of thrombosis and then increase after 3 hours of thrombosis, reaching levels higher than control animals. n = 6 samples/group. *P <.05 for controls versus thrombus 1-hour group, t test. Journal of Vascular Surgery 2001 34, 323-329DOI: (10.1067/mva.2001.115004) Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 5 EDR was measured after 1 hour of thrombosis and thrombolytic infusion. Urokinase (UK ) supplemented with 20 mmol/L of L -arginine (hi L-arg ) resulted in significantly higher EDR than UK alone or UK supplemented with 2 mmol/L of L -arginine (lo L-arg ). n = 8 to 10 samples/group. *P <.05, analysis of variance. Ach, Acetylcholine. Journal of Vascular Surgery 2001 34, 323-329DOI: (10.1067/mva.2001.115004) Copyright © 2001 Mosby, Inc. Terms and Conditions

Fig. 6 Local NOx levels increase after infusion of increasing L -arginine concentrations in thrombolytic regimen. Urokinase (UK ) supplemented with 20 mmol/L of L -arginine (hi L-arg ) results in 20-fold increase in local NOx levels (2.8 ± 0.52 μmol/L vs 0.133 ± 0.02 μmol/L. n = 6 samples/group. *P <.005, analysis of variance. lo L-arg, 2 mmol/L of L -arginine. Journal of Vascular Surgery 2001 34, 323-329DOI: (10.1067/mva.2001.115004) Copyright © 2001 Mosby, Inc. Terms and Conditions