The calcium sensitizer levosimendan attenuates endotoxin-evoked myocardial dysfunction in isolated guinea pig hearts.
OBJECTIVE
Sepsis-evoked myocardial dysfunction is possibly due to decreased myofilament calcium sensitivity, and a calcium sensitizer may thus specifically improve contractility in sepsis by enhancing myofilament calcium sensitivity. We examined whether the calcium sensitizer levosimendan mitigates myocardial dysfunction and improves contractility in hearts isolated from endotoxin-treated guinea pigs.


METHODS
Prospective, controlled, randomized animal study in a university research laboratory.


METHODS
Guinea pig hearts isolated 4 h (n=10) or 18 h (n=8) following E. coli LPS (4 mg/kg i.p.) and hearts from sham-treated controls (n=11 and n=6).


METHODS
Isolated hearts were perfused at constant aortic pressure [Krebs-Henseleit buffer, heart rate: 300/min, left ventricular (LV) diastolic pressure: 6-8 mmHg], and LV developed pressure (LVd P) and LVd P/d t were continuously assessed. Levosimendan was added to the perfusate in incremental concentrations (0.03, 0.1, 0.3 microM).


RESULTS
Endotoxin resulted in a significant decrease in LVd P by 20+/-6% and 43+/-8%, in +LVd P/d t by 16+/-5% and 44+/-7%, and in -LVd P/d t by 27+/-8% and 47+/-8% after 4 and 18 h, respectively. In septic hearts levosimendan increased LV function concentration-dependently by 32+/-4% (LVd P), 33+/-5% (+LVd P/d t), and 37+/-7% (-LVd P/d t) 4 h and by 31+/-6% (LVd P), 33+/-6% (+LVd P/d t), and 32+/-7% (-LVd P/d t) 18 h after LPS. However, levosimendan increased myocardial function similarly in control hearts.


CONCLUSIONS
While the calcium sensitizer levosimendan markedly improved LV contractility in hearts from both endotoxic and sham animals, it failed to specifically abolish endotoxin-evoked myocardial dysfunction. Thus, decreased calcium sensitivity either does not play a major role in endotoxin-evoked cardiomyopathy or the location of its pathomechanism differs from levosimendan's site of action.
Behrends
Matthias
M
Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany. matthias.behrends@uni-essen.de
Peters
Jürgen
J
D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006168:Guinea Pigs; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D008297:Male; D011446:Prospective Studies; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D000077464:Simendan; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D006835:Hydrazones; D008070:Lipopolysaccharides; D011724:Pyridazines; D000077464:Simendan