Cardioprotective and functional effects of levosimendan and milrinone in mice with cecal ligation and puncture-induced sepsis
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.
KeywordsCardiac inflammation Cardiac injury Inotropic agent Left ventricular function L-type calcium current Polymicrobial sepsis
This study was supported by Grant-in-Aids for Challenging Exploratory Research (15K15661) and for Scientific Research (17K08586, 17K11047) from Japan Society for Promotion of Science. The authors wish to thank Prof. Y. Maekawa and Dr. M. Saotome for giving K. Iguchi the opportunity to work at the Department of Health Science, Hamamatsu University School of Medicine. The authors are also grateful to Sailesh Palikhe for proofreading.
Y.W., N.M., N.Y., and Y.H. conceived and designed the experiments. S.Y., T. Suzuki., K.I., Y.W., T. Sakamoto, K.T., H.Y., M.S., H.M., and T.N. performed the experiments. S.Y., T. Suzuki, K.T., and Y.W. analyzed data. Y.W., T. Suzuki, K.H., and Y.H. wrote the article. All authors read and approved the manuscript.
Compliance and ethical standards
Conflict of interest
The authors report no conflict of interest.
All animal studies were approved by the Animal Care and Use Committee of the University of Toyama and the Animal Research Committee of Hamamatsu University School of Medicine, which are based on the National Institute of Health Guide for the Care and Use of Laboratory Animals and the ARRIVE guidelines.
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