Cardioprotective and functional effects of levosimendan and milrinone in mice with cecal ligation and puncture-induced sepsis

Abstract

Levosimendan and milrinone may be used in place of dobutamine to increase cardiac output in septic patients with a low cardiac output due to impaired cardiac function. The effects of the two inotropic agents on cardiac inflammation and left ventricular (LV) performance were examined in mice with cecal ligation and puncture (CLP)-induced sepsis. CLP mice displayed significant cardiac inflammation, as indicated by highly increased pro-inflammatory cytokines and neutrophil infiltration in myocardial tissues. When continuously given, levosimendan prevented but milrinone exaggerated cardiac inflammation, but they significantly reduced the elevations in plasma cardiac troponin-I and heart-type fatty acid-binding protein, clinical markers of cardiac injury. Echocardiographic assessment of cardiac function showed that the effect of levosimendan, given by an intravenous bolus injection, on LV performance was impaired in CLP mice, whereas milrinone produced inotropic responses equally in sham-operated and CLP mice. A lesser effect of levosimendan on LV performance after CLP was also found in spontaneously beating Langendorff-perfused hearts. In ventricular myocytes isolated from control and CLP mice, levosimendan, but not milrinone, caused a large increase in the L-type calcium current. This study represents that levosimendan and milrinone have cardioprotective properties but provide different advantages and drawbacks to cardiac inflammation/dysfunction in sepsis.

Vascular endothelial growth factor contributes to lung vascular hyperpermeability in sepsis-associated acute lung injury

“…CLP-induced sepsis is regarded as a highly clinically relevant model of polymicrobial sepsis, because it reproduces many hallmarks of sepsis occurring in human patients (Hubbard et al 2005 ). The surgical procedure to generate CLP-induced sepsis was conducted according to our previous reports (Tomita et al 2015 ; Kawakami et al 2018 ; Yamashita et al 2018 ). In brief, male BALB/c mice (Sankyo Lab Service, Tokyo Japan), 8–12 weeks old, were anesthetized with 3–4% sevoflurane by inhalation, and a middle abdominal incision was made.…”

“…Sham-operated control underwent the same procedure except for ligation and puncture of the cecum. Both groups of animals were fed the same diet and water ad libitum, and housed in an environment with controlled temperature, constant humidity, and a daily 12-h light-dark cycle (Yamashita et al 2018 ). All animals after CLP surgery were lethargic, showed lack of interest in their environment, displayed piloerection, and had crusty exudates around their eyes, as opposed to sham-operated animals that were healthy, moving freely and eating (Matsuda et al 2010 ).…”

Beneficial effect of STAT3 decoy oligodeoxynucleotide transfection on organ injury and mortality in mice with cecal ligation and puncture-induced sepsis

“…Both groups of animals were fed the same diet and water ad libitum. The animals after CLP surgery were all lethargic, showed lack of interest in their environment, displayed piloerection, and had crusty exudates around their eyes, as contrasted with sham-operated animals that were healthy, moving freely and eating 50 . Normal saline (0.5 ml) was given subcutaneously to all mice immediately after surgery.…”

“…The proteins in the supernatant were measured using BCA Protein Assay Kit (Nacalai Tesque, Kyoto, Japan). Immunoblotting was performed as described previously 48,50,53 . Samples (30-50 μg of protein) were electrophoresed on 10-14% SDS-PAGE and transferred to PVDF membrane.…”

“…Immunohistological examination was performed as described previously 50,53 . Tissue Sections (4 μm) were rehydrated, and endogenous peroxidases were quenched with 3% hydrogen peroxide.…”