Effect of creatine monohydrate on cardiac function in a rat model of endotoxemia.
BACKGROUND
Reports have attributed cardiac failure during acute models of endotoxemia to a lack of high-energy phosphates. This study was undertaken to investigate whether creatine (Cr) administered during perfusion could enhance myocardial protection and improve recovery of cardiac function in a rat model of endotoxemia.


METHODS
Acute endotoxemia was induced in rats by a bolus injection of Escherichia coli endotoxin (LPS: 4 mg/kg, ip) while control rats were injected with an equal volume of 0.9% normal saline. To assess the adequacy of energy metabolism, freeze-clamped hearts were obtained from animals to study the concentrations of endogenous ATP, phosphocreatine (PCr), inorganic phosphate (P(i)), and intracellular pH by (31)P-cryomagnetic resonance spectroscopy. In a separate experiment, isolated hearts were perfused via a Langendorff column with Krebs-Henseleit buffer containing different concentrations of creatine monohydrate (1, 3, or 10 mM). Cardiac performance was evaluated via a paced (300 bpm) isovolumetric balloon preparation. Measurements of cardiac function including left ventricular developed pressure (LVDP), the maximum rates of ventricular pressure rise (LV +dP/dt) and fall (LV -dP/dt), and coronary flow were made for both LPS and saline-treated animals.


RESULTS
High-energy phosphate ratios of PCr/ATP and PCr/P(i) in hearts declined significantly at 4 h after endotoxin treatment. As anticipated, LVDP and LV +dP/dt(max) at a given preload and heart rate were significantly (P < 0.05) lower at 4 h when measured at the same time point. The functional recovery of these parameters was not improved by the addition of creatine monohydrate to the perfusion buffer. Creatine produced a significant (P < 0.05) negative inotropic effect in hearts from saline-treated animals. The LVDP was reduced by 30% at the lowest concentration and by 50% at the highest concentration of creatine monohydrate. Furthermore, creatine significantly (P < 0.05) reduced LV -dP/dt(max) in both saline and LPS-treated rats. These data demonstrate that exogenous creatine does not contribute to myocardial preservation in endotoxemia.


CONCLUSIONS
Energy stores in the rat heart decline early in endotoxemia accompanied by reduced myocardial performance, suggesting that the ability of the heart to perform mechanical work is impaired. Cardiac dysfunction in an acute model of endotoxemia was not improved with exogenous creatine during perfusion. Creatine's effects were primarily lusitropic by delaying the onset of myocardial relaxation in all hearts. The deleterious effects of exogenous creatine monohydrate in normal hearts should be examined in future experimental studies.
Vona-Davis
L
L
Department of Surgery, West Virginia University, Morgantown, West Virginia 26506, USA. lvdavis@hsc.wvu.edu
Wearden
P D
PD
Karne
N H
NH
Hill
R C
RC
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology; D003401:Creatine / Q000494:pharmacology*; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000150:complications / Q000188:drug therapy*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D017725:Ventricular Pressure / Q000187:drug effects
D008070:Lipopolysaccharides; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D003401:Creatine