Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia
Prognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan...
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MDPI AG
2021-04-01
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| author | Carolin Torregroza Birce Yueksel Raphael Ruske Martin Stroethoff Annika Raupach André Heinen Markus W. Hollmann Ragnar Huhn Katharina Feige |
| author_facet | Carolin Torregroza Birce Yueksel Raphael Ruske Martin Stroethoff Annika Raupach André Heinen Markus W. Hollmann Ragnar Huhn Katharina Feige |
| author_sort | Carolin Torregroza |
| collection | DOAJ |
| description | Prognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan-induced postconditioning, a strong infarct size reducing effect is demonstrated in healthy myocardium. However, acute hyperglycemia is suggested to block this protective effect. In the present study, we investigated whether (1) Levosimendan-induced postconditioning exerts a concentration-dependent effect under hyperglycemic conditions and (2) whether a combination with the mitochondrial permeability transition pore (mPTP) blocker cyclosporine A (CsA) restores the cardioprotective properties of Levosimendan under hyperglycemia. For this experimental investigation, hearts of male Wistar rats were randomized and mounted onto a Langendorff system, perfused with Krebs-Henseleit buffer with a constant pressure of 80 mmHg. All isolated hearts were subjected to 33 min of global ischemia and 60 min of reperfusion under hyperglycemic conditions. (1) Hearts were perfused with various concentrations of Levosimendan (Lev) (0.3–10 μM) for 10 min at the onset of reperfusion, in order to investigate a concentration–response relationship. In the second set of experiments (2), 0.3 μM Levosimendan was administered in combination with the mPTP blocker CsA, to elucidate the underlying mechanism of blocked cardioprotection under hyperglycemia. Infarct size was determined by tetrazolium chloride (TTC) staining. (1) Control (Con) hearts showed an infarct size of 52 ± 12%. None of the administered Levosimendan concentrations reduced the infarct size (Lev0.3: 49 ± 9%; Lev1: 57 ± 9%; Lev3: 47 ± 11%; Lev10: 50 ± 7%; all ns vs. Con). (2) Infarct size of Con and Lev0.3 hearts were 53 ± 4% and 56 ± 2%, respectively. CsA alone had no effect on infarct size (CsA: 50 ± 10%; ns vs. Con). The combination of Lev0.3 and CsA (Lev0.3 ± CsA) induced a significant infarct size reduction compared to Lev0.3 (Lev0.3+CsA: 35 ± 4%; <i>p</i> < 0.05 vs. Lev0.3). We demonstrated that (1) hyperglycemia blocks the infarct size reducing effects of Levosimendan-induced postconditioning and cannot be overcome by an increased concentration. (2) Furthermore, cardioprotection under hyperglycemia can be restored by combining Levosimendan and the mPTP blocker CsA. |
| first_indexed | 2024-03-10T11:57:02Z |
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| language | English |
| last_indexed | 2024-03-10T11:57:02Z |
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| spelling | doaj.art-6681e6261a444cbcbe9976728deded732023-11-21T17:13:54ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01229451710.3390/ijms22094517Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute HyperglycemiaCarolin Torregroza0Birce Yueksel1Raphael Ruske2Martin Stroethoff3Annika Raupach4André Heinen5Markus W. Hollmann6Ragnar Huhn7Katharina Feige8Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyDepartment of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyDepartment of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyDepartment of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyDepartment of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyInstitute of Cardiovascular Physiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, GermanyDepartment of Anesthesiology, Amsterdam University Medical Center (AUMC), Location AMC, Meiberdreef 9, 1105 AZ Amsterdam, The NetherlandsDepartment of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyDepartment of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, GermanyPrognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan-induced postconditioning, a strong infarct size reducing effect is demonstrated in healthy myocardium. However, acute hyperglycemia is suggested to block this protective effect. In the present study, we investigated whether (1) Levosimendan-induced postconditioning exerts a concentration-dependent effect under hyperglycemic conditions and (2) whether a combination with the mitochondrial permeability transition pore (mPTP) blocker cyclosporine A (CsA) restores the cardioprotective properties of Levosimendan under hyperglycemia. For this experimental investigation, hearts of male Wistar rats were randomized and mounted onto a Langendorff system, perfused with Krebs-Henseleit buffer with a constant pressure of 80 mmHg. All isolated hearts were subjected to 33 min of global ischemia and 60 min of reperfusion under hyperglycemic conditions. (1) Hearts were perfused with various concentrations of Levosimendan (Lev) (0.3–10 μM) for 10 min at the onset of reperfusion, in order to investigate a concentration–response relationship. In the second set of experiments (2), 0.3 μM Levosimendan was administered in combination with the mPTP blocker CsA, to elucidate the underlying mechanism of blocked cardioprotection under hyperglycemia. Infarct size was determined by tetrazolium chloride (TTC) staining. (1) Control (Con) hearts showed an infarct size of 52 ± 12%. None of the administered Levosimendan concentrations reduced the infarct size (Lev0.3: 49 ± 9%; Lev1: 57 ± 9%; Lev3: 47 ± 11%; Lev10: 50 ± 7%; all ns vs. Con). (2) Infarct size of Con and Lev0.3 hearts were 53 ± 4% and 56 ± 2%, respectively. CsA alone had no effect on infarct size (CsA: 50 ± 10%; ns vs. Con). The combination of Lev0.3 and CsA (Lev0.3 ± CsA) induced a significant infarct size reduction compared to Lev0.3 (Lev0.3+CsA: 35 ± 4%; <i>p</i> < 0.05 vs. Lev0.3). We demonstrated that (1) hyperglycemia blocks the infarct size reducing effects of Levosimendan-induced postconditioning and cannot be overcome by an increased concentration. (2) Furthermore, cardioprotection under hyperglycemia can be restored by combining Levosimendan and the mPTP blocker CsA.https://www.mdpi.com/1422-0067/22/9/4517Levosimendanhyperglycemiamyocardial infarctioncardioprotection |
| spellingShingle | Carolin Torregroza Birce Yueksel Raphael Ruske Martin Stroethoff Annika Raupach André Heinen Markus W. Hollmann Ragnar Huhn Katharina Feige Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia International Journal of Molecular Sciences Levosimendan hyperglycemia myocardial infarction cardioprotection |
| title | Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia |
| title_full | Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia |
| title_fullStr | Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia |
| title_full_unstemmed | Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia |
| title_short | Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia |
| title_sort | combination of cyclosporine a and levosimendan induces cardioprotection under acute hyperglycemia |
| topic | Levosimendan hyperglycemia myocardial infarction cardioprotection |
| url | https://www.mdpi.com/1422-0067/22/9/4517 |
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