The effect of diazepam on myocardial function and coronary vascular tone after endotoxemia in the isolated rat heart model.
OBJECTIVE
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.


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.
Neethling
William M L
WM
Fremantle Heart Institute, Fremantle Hospital, School of Surgery and Pathology, University of Western Australia, Fremantle, WA, Australia. Leon.Neethling@health.wa.gov.au
Hodge
Andrew J
AJ
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000139:chemically induced / Q000503:physiopathology*; D018757:GABA Modulators / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018757:GABA Modulators; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003975:Diazepam