The calcium sensitizer levosimendan attenuates endotoxin-evoked myocardial dysfunction in isolated guinea pig hearts
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- Behrends, M. & Peters, J. Intensive Care Med (2003) 29: 1802. doi:10.1007/s00134-003-1879-8
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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.
Design and setting
Prospective, controlled, randomized animal study in a university research laboratory.
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).
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 (LVdP) and LVdP/dt were continuously assessed. Levosimendan was added to the perfusate in incremental concentrations (0.03, 0.1, 0.3 µM).
Measurements and results
Endotoxin resulted in a significant decrease in LVdP by 20±6% and 43±8%, in +LVdP/dt by 16±5% and 44±7%, and in −LVdP/dt by 27±8% and 47±8% after 4 and 18 h, respectively. In septic hearts levosimendan increased LV function concentration-dependently by 32±4% (LVdP), 33±5% (+LVdP/dt), and 37±7% (−LVdP/dt) 4 h and by 31±6% (LVdP), 33±6% (+LVdP/dt), and 32±7% (−LVdP/dt) 18 h after LPS. However, levosimendan increased myocardial function similarly in control hearts.
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.