Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 22, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp097
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Antithrombin reduces shedding of the endothelial glycocalyx following ischemia/reperfusion
1 Clinic of Anesthesiology, Ludwig-Maximilians-University Munich
2 Institute of Anatomy, Ludwig-Maximilians-University Munich
3 Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University Munich
Corresponding author: Dr. Daniel Chappell, Clinic of Anesthesiology, Ludwig-Maximilians-University Munich, Nussbaumstrasse 20, 80336 Munich, Germany, Tel.: +49-89-2180-75382, Fax: +49-89-5160-4446, E-mail: daniel.chappell{at}med.uni-muenchen.de
Aims: Antithrombin is an important inhibitor of the coagulation system, additionally exerting specific anti-inflammatory effects on endothelial cells. Healthy vascular endothelium is coated by the endothelial glycocalyx, diminution of which increases capillary permeability, e.g., after ischemia. Antithrombin is known to infiltrate the glycocalyx, binding to glycosaminoglycans, and to preserve the glycocalyx after application tumor necrosis factor-
. We investigated the influence of antithrombin on glycocalyx subjected to ischemia/reperfusion.
Methods: Isolated guinea pig hearts were perfused with Krebs-Henseleit buffer (KHB). Antithrombin was applied to achieve physiological levels (1 U/ml) before inducing 20 min of ischemia (37°C). Hearts were reperfused for 20 min at constant flow (baseline perfusion pressure 70cmH2O) with KHB or KHB plus 2 g% hydroxyethylstarch (130kD). Coronary net fluid filtration was assessed directly by measuring transudate formation on the epicardial surface. Postischemic coronary release of syndecan-1 and heparan sulfate was quantified by ELISA. Hearts were perfusion-fixed to visualize the glycocalyx by electron microscopy.
Results: Ischemia/reperfusion caused degradation of the glycocalyx, enhanced coronary perfusion pressure and increased vascular permeability. Antithrombin significantly reduced postischemic glycocalyx shedding, coronary perfusion pressure, coronary leak and tissue edema formation compared to untreated hearts. Additional application of colloid augmented these actions of antithrombin. Electron microscopy revealed a mostly intact glycocalyx after antithrombin treatment.
Conclusions: Antithrombin preserves the endothelial glycocalyx, sustaining the vascular barrier function and reducing interstitial edema. The potentiated effect of colloid in these hearts suggests that the prevention of shedding should be of functional benefit also in vivo.
KEYWORDS Endothelial function; Ischemia; Antithrombin; Glycocalyx; Vascular leak
Time for primary review: 40 Days
The work was performed at: Clinic of Anesthesiology and Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany.