William M L Neethling1, Andrew J Hodge. 1. Fremantle Heart Institute, Fremantle Hospital, School of Surgery and Pathology, University of Western Australia, Fremantle, WA, Australia. Leon.Neethling@health.wa.gov.au
Abstract
OBJECTIVE AND DESIGN: Tumor necrosis factor alpha (TNF-α) has been implicated in the pathogenesis of cardiovascular disease and sepsis-associated cardiac dysfunction. Although initially described solely as a lipopolysaccharide (LPS)-induced macrophage product, evidence exists that cardiac myocytes themselves produce substantial amounts of TNF-α in response to ischemia as well as LPS. The use of phosphodiesterase inhibitors has been shown to decrease LPS-induced TNF-α elaboration. The aim of the present study was to determine the effect of diazepam (Type IV phosphodiesterase inhibitor) on (1) myocardial function and (2) coronary vascular flow after LPS-induced endotoxic shock in an isolated rat heart model. MATERIALS AND METHODS: Endotoxemia was induced by intraperitoneal LPS administration in adult male Wistar rats. Hearts were isolated after 6 h and perfused in a working mode with oxygenated Krebs-Henseleit buffer at 37°C. Diazepam was mixed with Krebs-Henseleit buffer and administered (3.0 μg/ml) for 20 min. RESULTS: LPS-treated hearts showed depressed cardiac function and reduced coronary flow. Myocardial functional parameters (LVDP, +dP/dt, -dP/dt, RPP) and coronary flow (ml/min) were significantly (p < 0.01) improved by diazepam administration. CONCLUSIONS: These findings suggest that diazepam can salvage myocardial function and undo coronary vascular constriction in the endotoxemic rat heart. These findings are clinically relevant to the treatment of cardiovascular depression caused by endotoxic shock.
OBJECTIVE AND DESIGN:Tumor necrosis factor alpha (TNF-α) has been implicated in the pathogenesis of cardiovascular disease and sepsis-associated cardiac dysfunction. Although initially described solely as a lipopolysaccharide (LPS)-induced macrophage product, evidence exists that cardiac myocytes themselves produce substantial amounts of TNF-α in response to ischemia as well as LPS. The use of phosphodiesterase inhibitors has been shown to decrease LPS-induced TNF-α elaboration. The aim of the present study was to determine the effect of diazepam (Type IV phosphodiesterase inhibitor) on (1) myocardial function and (2) coronary vascular flow after LPS-induced endotoxic shock in an isolated rat heart model. MATERIALS AND METHODS:Endotoxemia was induced by intraperitoneal LPS administration in adult male Wistar rats. Hearts were isolated after 6 h and perfused in a working mode with oxygenated Krebs-Henseleit buffer at 37°C. Diazepam was mixed with Krebs-Henseleit buffer and administered (3.0 μg/ml) for 20 min. RESULTS:LPS-treated hearts showed depressed cardiac function and reduced coronary flow. Myocardial functional parameters (LVDP, +dP/dt, -dP/dt, RPP) and coronary flow (ml/min) were significantly (p < 0.01) improved by diazepam administration. CONCLUSIONS: These findings suggest that diazepam can salvage myocardial function and undo coronary vascular constriction in the endotoxemic rat heart. These findings are clinically relevant to the treatment of cardiovascular depression caused by endotoxic shock.
Authors: Sidi Mohammed Hassoun; Xavier Marechal; David Montaigne; Youcef Bouazza; Brigitte Decoster; Steve Lancel; Remi Neviere Journal: Crit Care Med Date: 2008-09 Impact factor: 7.598
Authors: K A Krown; K Yasui; M J Brooker; A E Dubin; C Nguyen; G L Harris; P M McDonough; C C Glembotski; P T Palade; R A Sabbadini Journal: FEBS Lett Date: 1995-11-27 Impact factor: 4.124
Authors: Fadi H Khadour; Donna Panas; Péter Ferdinandy; Costas Schulze; Tamás Csont; Manoj M Lalu; Stephen M Wildhirt; Richard Schulz Journal: Am J Physiol Heart Circ Physiol Date: 2002-09 Impact factor: 4.733