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. 2022 Aug 12;9(8):263.
doi: 10.3390/jcdd9080263.

The Coadministration of Levosimendan and Exenatide Offers a Significant Cardioprotective Effect to Isolated Rat Hearts against Ischemia/Reperfusion Injury

Vasileios Leivaditis  1   2 , Efstratios Koletsis  2 , Nikolaos Tsopanoglou  3 , Nikolaos Charokopos  2 , Cristian D'Alessandro  4 , Konstantinos Grapatsas  5 , Efstratios Apostolakis  6 , Effrosyni Choleva  7 , Maria Plota  8 , Andreas Emmanuil  9 , Manfred Dahm  1 , Dimitrios Dougenis  10
Affiliations

The Coadministration of Levosimendan and Exenatide Offers a Significant Cardioprotective Effect to Isolated Rat Hearts against Ischemia/Reperfusion Injury

Vasileios Leivaditis et al. J Cardiovasc Dev Dis. .

Abstract

(1) Background: The present study aims to investigate the effect of administration of Levosimendan and Exenatide in various concentrations, as well as of the coadministration of those agents in an ischemia-reperfusion injury isolated heart model. (2) Methods: After 30 min of perfusion, the hearts underwent a 30 min period of regional ischemia followed by a 120 min period of reperfusion. All animals were randomly divided into 12 experimental groups of nine animals in each group: (1) Control, (2) Sham, (3) Digox (Negative control, Digoxin 1.67 μg/min), (4) Levo 1 (Levosimendan 0.01 μg/min), (5) Levo 2 (Levosimendan 0.03 μg/mL), (6) Levo 3 (Levosimendan 0.1 μg/min), (7) Levo 4 (Levosimendan 0.3 μg/min), (8) Levo 5 (Levosimendan 1 μg/min), (9) Exen 1 (Exenatide 0.001 μg/min), (10) Exen 2 (Exenatide 0.01 μg/min), (11) Exen 3 (Exenatide 0.1 μg/min) and (12) Combi (Levosimendan 0.1 µg/mL + Exenatide 0.001 μg/min). The hemodynamic parameters were recorded throughout the experiment. Arrhythmias and coronary flow were also evaluated. After every experiment the heart was suitably prepared and infarct size was measured. Markers of myocardial injury were also measured. Finally, oxidative stress was evaluated measuring reactive oxygen species. (3) Results: A dose-dependent improvement of the haemodynamic response was observed after the administration of both Levosimendan and Exenatide. The coadministration of both agents presented an even greater effect, improving the haemodynamic parameters further than the two agents separately. Levosimendan offered an increase of the coronary flow and both agents offered a reduction of arrhythmias. A dose-dependent reduction of the size of myocardial infarction and myocardial injury was observed after administration of Levosimendan and Exenatide. The coadministration of both agents offered a further improving the above parameters. Levosimendan also offered a significant reduction of oxidative stress. (4) Conclusions: The administration of Levosimendan and Exenatide offers a significant benefit by improving the haemodynamic response, increasing the coronary flow and reducing the occurrence of arrhythmias, the size of myocardial injury and myocardial oxidative stress in isolated rat hearts.

Keywords: Exenatide; Levosimendan; cardioprotection; ischemia-reperfusion injury; isolated rat heart.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic demonstration of the experimental protocol showing the groups and the durations of the three phases of the experiment (perfusion, ischemia and reperfusion). The application of the treatment started at the middle of the ischemia phase and was continued until the end of the reperfusion phase.
Figure 2
Figure 2
Schematic representation of the heart section with the measured areas. T = total area of the section, R = area at risk (area perfused by the LAD) and I = infarct area.
Figure 3
Figure 3
Changes in LVSP across groups over time.
Figure 4
Figure 4
Changes in LVEDP across groups over time.
Figure 5
Figure 5
Changes in LVDP across groups over time.
Figure 6
Figure 6
Changes in heart rate across groups over time.
Figure 7
Figure 7
Changes in RPP across groups over time.
Figure 8
Figure 8
Changes in +dP/dt across groups over time.
Figure 9
Figure 9
Changes in −dP/dt across groups over time.
Figure 10
Figure 10
Changes in coronary flow across groups over time.
Figure 11
Figure 11
Differences in arrhythmias score across groups.
Figure 12
Figure 12
Changes in Troponin across groups over time.
Figure 13
Figure 13
Changes in CK-MB across groups over time.
Figure 14
Figure 14
Changes in LDH across groups over time.
Figure 15
Figure 15
Sections of the hearts of all groups.
Figure 16
Figure 16
Changes in R/T across groups.
Figure 17
Figure 17
Changes in I/R across groups.
Figure 18
Figure 18
Differences in Reactive Oxygen Species across groups.
See this image and copyright information in PMC

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References

    1. Papp Z., Édes I., Fruhwald S., De Hert S.G., Salmenperä M., Leppikangas H., Mebazaa A., Landoni G., Grossini E., Caimmi P., et al. Levosimendan: Molecular mechanisms and clinical implications: Consensus of experts on the mechanisms of action of levosimendan. Int. J. Cardiol. 2012;159:82–87. doi: 10.1016/j.ijcard.2011.07.022. - DOI - PubMed
    1. Sorsa T., Pollesello P., Solaro R.J. The contractile apparatus as a target for drugs against heart failure: Interaction of levosimendan, a calcium sensitiser, with cardiac troponin c. Mol. Cell. Biochem. 2004;266:87–107. doi: 10.1023/B:MCBI.0000049141.37823.19. - DOI - PubMed
    1. Robertson I.M., Baryshnikova O.K., Li M.X., Sykes B.D. Defining the binding site of levosimendan and its analogues in a regulatory cardiac troponin C-troponin I complex. Biochemistry. 2008;7:7485–7495. doi: 10.1021/bi800438k. - DOI - PMC - PubMed
    1. Kaheinen P., Pollesello P., Levijoki J., Haikala H. Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels. J. Cardiovasc. Pharmacol. 2001;37:367–374. doi: 10.1097/00005344-200104000-00003. - DOI - PubMed
    1. Ozdem S.S., Yalcin O., Meiselman H.J., Baskurt O.K., Usta C. The role of potassium channels in relaxant effect of levosimendan in rat small mesenteric arteries. Cardiovasc. Drugs Ther. 2006;20:123–127. doi: 10.1007/s10557-006-7294-y. - DOI - PubMed

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