{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:28Z","timestamp":1787028448226,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:00:00Z","timestamp":1619395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u201310 \u03bcM) for 10 min at the onset of reperfusion, in order to investigate a concentration\u2013response relationship. In the second set of experiments (2), 0.3 \u03bcM 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 \u00b1 12%. None of the administered Levosimendan concentrations reduced the infarct size (Lev0.3: 49 \u00b1 9%; Lev1: 57 \u00b1 9%; Lev3: 47 \u00b1 11%; Lev10: 50 \u00b1 7%; all ns vs. Con). (2) Infarct size of Con and Lev0.3 hearts were 53 \u00b1 4% and 56 \u00b1 2%, respectively. CsA alone had no effect on infarct size (CsA: 50 \u00b1 10%; ns vs. Con). The combination of Lev0.3 and CsA (Lev0.3 \u00b1 CsA) induced a significant infarct size reduction compared to Lev0.3 (Lev0.3+CsA: 35 \u00b1 4%; p &lt; 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.<\/jats:p>","DOI":"10.3390\/ijms22094517","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T02:31:43Z","timestamp":1619490703000},"page":"4517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia"],"prefix":"10.3390","volume":"22","author":[{"given":"Carolin","family":"Torregroza","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birce","family":"Yueksel","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Ruske","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Stroethoff","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5257-1022","authenticated-orcid":false,"given":"Annika","family":"Raupach","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Heinen","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Physiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus W.","family":"Hollmann","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Amsterdam University Medical Center (AUMC), Location AMC, Meiberdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragnar","family":"Huhn","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Feige","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e008407","DOI":"10.1161\/JAHA.117.008407","article-title":"Improving Outcomes after Myocardial Infarction in the US Population","volume":"7","author":"Kayani","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_2","unstructured":"World Health Organization (2021, March 09). The 10 Leading Causes of Death in the World, 2000 and 2012. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/the-top-10-causes-of-death."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.jacc.2019.12.026","article-title":"Readmission and Mortality After Hospitalization for Myocardial Infarction and Heart Failure","volume":"75","author":"Ko","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1016\/j.amjcard.2013.06.007","article-title":"Relation of admission glucose levels, short- and long-term (20-year) mortality after acute myocardial infarction","volume":"112","author":"Deckers","year":"2013","journal-title":"Am. J. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1097\/00019501-199610000-00006","article-title":"Outcomes of diabetic patients following acute myocardial infarction: A review of the major thrombolytic trials","volume":"7","author":"Jelesoff","year":"1996","journal-title":"Coron. Artery Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/0002-9149(89)90836-9","article-title":"Hyperglycemia and prognosis of acute myocardial infarction in patients without diabetes mellitus","volume":"64","author":"Bellodi","year":"1989","journal-title":"Am. J. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.2337\/db14-0571","article-title":"Hyperglycemia and Adverse Outcomes in Acute Coronary Syndromes: Is Serum Glucose the Provocateur or Innocent Bystander?","volume":"63","author":"Wei","year":"2014","journal-title":"Diabetes"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1161\/CIRCULATIONAHA.108.837765","article-title":"Differential clinical outcomes associated with hypoglycemia and hyperglycemia in acute myocardial infarction","volume":"120","author":"Goyal","year":"2009","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.jacc.2010.05.008","article-title":"Treatments, trends, and outcomes of acute myocardial infarction and percutaneous coronary intervention","volume":"56","author":"Roe","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1172\/JCI62874","article-title":"Myocardial ischemia-reperfusion injury: A neglected therapeutic target","volume":"123","author":"Hausenloy","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"H579","DOI":"10.1152\/ajpheart.01064.2002","article-title":"Inhibition of myocardial injury by ischemic postconditioning during reperfusion: Comparison with ischemic preconditioning","volume":"285","author":"Zhao","year":"2003","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bunte, S., Behmenburg, F., Majewski, N., Stroethoff, M., Raupach, A., Mathes, A., Heinen, A., Hollmann, M.W., and Huhn, R. (2019). Characteristics of Dexmedetomidine Postconditioning in the Field of Myocardial Ischemia-Reperfusion Injury. Anesth. Analg.","DOI":"10.1213\/ANE.0000000000004417"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bja\/aeq213","article-title":"Ischaemic and morphine-induced post-conditioning: Impact of mK(Ca) channels","volume":"105","author":"Huhn","year":"2010","journal-title":"Br. J. Anaesth."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s10557-019-06908-7","article-title":"Impact of Ca(2+)-Sensitive Potassium Channels in Levosimendan-Induced Postconditioning","volume":"33","author":"Stroethoff","year":"2019","journal-title":"Cardiovasc. Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1097\/00000539-200001000-00003","article-title":"Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels","volume":"90","author":"Kersten","year":"2000","journal-title":"Anesth. Analg."},{"key":"ref_16","first-page":"125","article-title":"Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass","volume":"17","author":"Levin","year":"2012","journal-title":"Exp. Clin. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ijcard.2011.07.022","article-title":"Levosimendan: Molecular mechanisms and clinical implications: Consensus of experts on the mechanisms of action of levosimendan","volume":"159","author":"Papp","year":"2012","journal-title":"Int. J. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/bjp.2008.52","article-title":"A role for the RISK pathway and K(ATP) channels in pre- and post-conditioning induced by levosimendan in the isolated guinea pig heart","volume":"154","author":"Genis","year":"2008","journal-title":"Br. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s10557-018-6819-5","article-title":"Preconditioning by Levosimendan is Mediated by Activation of Mitochondrial Ca(2+)-Sensitive Potassium (mBKCa) Channels","volume":"32","author":"Bunte","year":"2018","journal-title":"Cardiovasc. Drugs"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00395-009-0064-9","article-title":"Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-III inhibition","volume":"105","author":"Theuring","year":"2010","journal-title":"Basic Res. Cardiol."},{"key":"ref_21","first-page":"505","article-title":"Levosimendan: Effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia\/reperfusion in the Langendorff-perfused guinea pig heart","volume":"290","author":"Muller","year":"1999","journal-title":"J. Pharm. Exp."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1093\/bja\/aen022","article-title":"Hyperglycaemia blocks sevoflurane-induced postconditioning in the rat heart in vivo: Cardioprotection can be restored by blocking the mitochondrial permeability transition pore","volume":"100","author":"Huhn","year":"2008","journal-title":"Br. J. Anaesth."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1097\/FJC.0b013e3181d26583","article-title":"Hyperglycemia inhibits anesthetic-induced postconditioning in the rabbit heart via modulation of phosphatidylinositol-3-kinase\/Akt and endothelial nitric oxide synthase signaling","volume":"55","author":"Raphael","year":"2010","journal-title":"J. Cardiovasc. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Torregroza, C., Feige, K., Schneider, L., Bunte, S., Stroethoff, M., Heinen, A., Hollmann, M.W., Huhn, R., and Raupach, A. (2020). Influence of Hyperglycemia on Dexmedetomidine-Induced Cardioprotection in the Isolated Perfused Rat Heart. J. Clin. Med., 9.","DOI":"10.3390\/jcm9051445"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s12933-015-0313-1","article-title":"Acute hyperglycemia abolishes cardioprotection by remote ischemic perconditioning","volume":"14","author":"Baranyai","year":"2015","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Goergens, J.I., Heinen, N.M., Zoller, J., Preckel, B., Bauer, I., Huhn, R., Ebel, D., and Raupach, A. (2019). Influence of Hyperglycemia During Different Phases of Ischemic Preconditioning on Cardioprotection-A Focus on Apoptosis and Aggregation of Granulocytes. Shock.","DOI":"10.1097\/SHK.0000000000001406"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.jss.2011.01.018","article-title":"Hyperglycemia attenuates myocardial preconditioning of remifentanil","volume":"174","author":"Kim","year":"2012","journal-title":"J. Surg. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5312","DOI":"10.1111\/bph.14993","article-title":"Effect of hyperglycaemia and diabetes on acute myocardial ischaemia\u2013reperfusion injury and cardioprotection by ischaemic conditioning protocols","volume":"177","author":"Penna","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1475-2840-11-4","article-title":"Hyperglycemia raises the threshold of levosimendan- but not milrinone-induced postconditioning in rat hearts","volume":"11","author":"Matsumoto","year":"2012","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"H1215","DOI":"10.1152\/ajpheart.00124.2018","article-title":"Mitochondria \u201cTHE\u201d target of myocardial conditioning","volume":"315","author":"Boengler","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s10741-007-9028-z","article-title":"Mitochondria and cardioprotection","volume":"12","author":"Lisa","year":"2007","journal-title":"Heart Fail. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/j.bbamcr.2011.01.031","article-title":"The mitochondrial permeability transition pore and cyclophilin D in cardioprotection","volume":"1813","author":"Carpi","year":"2011","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S0022-2828(03)00043-9","article-title":"The mitochondrial permeability transition pore: Its fundamental role in mediating cell death during ischaemia and reperfusion","volume":"35","author":"Hausenloy","year":"2003","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1213\/ANE.0000000000005243","article-title":"Perioperative Cardioprotection: General Mechanisms and Pharmacological Approaches","volume":"131","author":"Torregroza","year":"2020","journal-title":"Anesth. Analg."},{"key":"ref_35","first-page":"H721","article-title":"Acute hyperglycemia abolishes ischemic preconditioning in vivo","volume":"275","author":"Kersten","year":"1998","journal-title":"Am. J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ejphar.2008.07.010","article-title":"Blockade of anaesthetic-induced preconditioning in the hyperglycaemic myocardium: The regulation of different mitogen-activated protein kinases","volume":"592","author":"Weber","year":"2008","journal-title":"Eur. J. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1161\/CIRCRESAHA.117.310820","article-title":"Critical Issues for the Translation of Cardioprotection","volume":"120","author":"Heusch","year":"2017","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1213\/ANE.0000000000005234","article-title":"Perioperative Cardioprotection: Clinical Implications","volume":"131","author":"Roth","year":"2020","journal-title":"Anesth. Analg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"H1744","DOI":"10.1152\/ajpheart.2001.280.4.H1744","article-title":"Diabetes and hyperglycemia impair activation of mitochondrial K(ATP) channels","volume":"280","author":"Kersten","year":"2001","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9836302","DOI":"10.1155\/2019\/9836302","article-title":"Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K\/Akt and JAK2\/STAT3 Signaling","volume":"2019","author":"Lei","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.2337\/diabetes.54.8.2360","article-title":"Preconditioning the Diabetic Heart: The Importance of Akt Phosphorylation","volume":"54","author":"Tsang","year":"2005","journal-title":"Diabetes"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/00000542-200201000-00032","article-title":"Hyperglycemia prevents isoflurane-induced preconditioning against myocardial infarction","volume":"96","author":"Kehl","year":"2002","journal-title":"Anesthesiology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"535","DOI":"10.2165\/00003088-200746070-00001","article-title":"Clinical pharmacology of levosimendan","volume":"46","author":"Antila","year":"2007","journal-title":"Clin. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"I2","DOI":"10.1093\/eurheartj\/suy039","article-title":"Use of levosimendan in acute heart failure","volume":"20","author":"Harjola","year":"2018","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1046\/j.1365-2125.2003.01778.x","article-title":"Population pharmacokinetics of levosimendan in patients with congestive heart failure","volume":"55","author":"Jonsson","year":"2003","journal-title":"Br. J. Clin. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1085\/jgp.200709874","article-title":"How ATP inhibits the open K(ATP) channel","volume":"132","author":"Craig","year":"2008","journal-title":"J. Gen. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0005-2728(03)00109-9","article-title":"Mitochondrial potassium transport: The role of the mitochondrial ATP-sensitive K+ channel in cardiac function and cardioprotection","volume":"1606","author":"Garlid","year":"2003","journal-title":"Biochim. Biophys. Acta (BBA) Bioenerg."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1089\/ars.2005.7.1476","article-title":"Hyperglycemia-induced reactive oxygen species and impaired endothelial progenitor cell function","volume":"7","author":"Callaghan","year":"2005","journal-title":"Antioxid. Redox Signal."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"H874","DOI":"10.1152\/ajpheart.01189.2007","article-title":"Intramitochondrial signaling: Interactions among mitoKATP, PKCepsilon, ROS, and MPT","volume":"295","author":"Costa","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1097\/00000542-200306000-00013","article-title":"N-acetylcysteine restores isoflurane-induced preconditioning against myocardial infarction during hyperglycemia","volume":"98","author":"Kehl","year":"2003","journal-title":"Anesthesiology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s12933-017-0527-5","article-title":"Glycemia and the cardioprotective effects of insulin pre-conditioning in the isolated rat heart","volume":"16","author":"Nakadate","year":"2017","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jacc.2018.09.086","article-title":"Multitarget Strategies to Reduce Myocardial Ischemia\/Reperfusion Injury: JACC Review Topic of the Week","volume":"73","author":"Davidson","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.yjmcc.2004.12.001","article-title":"Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury","volume":"38","author":"Argaud","year":"2005","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/S0008-6363(02)00455-8","article-title":"Inhibiting mitochondrial permeability transition pore opening: A new paradigm for myocardial preconditioning?","volume":"55","author":"Hausenloy","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/978-1-4939-8597-5_8","article-title":"Langendorff Perfusion Method as an Ex Vivo Model to Evaluate Heart Function in Rats","volume":"1816","author":"Watanabe","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s10557-009-6176-5","article-title":"One hour reperfusion is enough to assess function and infarct size with TTC staining in Langendorff rat model","volume":"23","author":"Ferrera","year":"2009","journal-title":"Cardiovasc. Drugs"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Feige, K., Rubbert, J., Raupach, A., Stroethoff, M., Heinen, A., Hollmann, M.W., Huhn, R., and Torregroza, C. (2021). Cardioprotective Properties of Mannitol-Involvement of Mitochondrial Potassium Channels. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052395"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Behmenburg, F., Dorsch, M., Huhn, R., Mally, D., Heinen, A., Hollmann, M.W., and Berger, M.M. (2015). Impact of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels in Sildenafil-Induced Cardioprotection in Rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0144737"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s10557-020-06972-4","article-title":"The Melatonin Receptor Agonist Ramelteon Induces Cardioprotection that Requires MT2 Receptor Activation and Release of Reactive Oxygen Species","volume":"34","author":"Stroethoff","year":"2020","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Raupach, A., Reinle, J., Stroethoff, M., Mathes, A., Heinen, A., Hollmann, M.W., Huhn, R., and Bunte, S. (2019). Milrinone-Induced Pharmacological Preconditioning in Cardioprotection: Hints for a Role of Mitochondrial Mechanisms. J. Clin. Med., 8.","DOI":"10.3390\/jcm8040507"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4517\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:52:59Z","timestamp":1760161979000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4517"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,26]]},"references-count":60,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22094517"],"URL":"https:\/\/doi.org\/10.3390\/ijms22094517","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,26]]}}}