Cardioprotective Properties of Mannitol-Involvement of Mitochondrial Potassium Channels

Katharina Feige; Janine Rubbert; Annika Raupach; Martin Stroethoff; André Heinen; Markus W Hollmann; Ragnar Huhn; Carolin Torregroza

doi:10.3390/ijms22052395

Cardioprotective Properties of Mannitol-Involvement of Mitochondrial Potassium Channels

Int J Mol Sci. 2021 Feb 27;22(5):2395. doi: 10.3390/ijms22052395.

Authors

Katharina Feige¹, Janine Rubbert¹, Annika Raupach¹, Martin Stroethoff¹, André Heinen², Markus W Hollmann³, Ragnar Huhn¹, Carolin Torregroza¹

Affiliations

¹ Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
² Institute of Cardiovascular Physiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
³ Department of Anesthesiology, Amsterdam University Medical Center (AUMC), Location AMC, Meiberdreef 9, 1105 AZ Amsterdam, The Netherlands.

Abstract

Cardiac preconditioning (PC) and postconditioning (PoC) are powerful measures against the consequences of myocardial ischemia and reperfusion (I/R) injury. Mannitol-a hyperosmolar solution-is clinically used for treatment of intracranial and intraocular pressure or promotion of diuresis in renal failure. Next to these clinical indications, different organ-protective properties-e.g., perioperative neuroprotection-are described. However, whether Mannitol also confers cardioprotection via a pre- and/or postconditioning stimulus, possibly reducing consequences of I/R injury, remains to be seen. Therefore, in the present study we investigated whether (1) Mannitol-induced pre- and/or postconditioning induces myocardial infarct size reduction and (2) activation of mitochondrial ATP-sensitive potassium (mK_ATP) channels is involved in cardioprotection by Mannitol. Experiments were performed on isolated hearts of male Wistar rats via a pressure controlled Langendorff system, randomized into 7 groups. Each heart underwent 33 min of global ischemia and 60 min of reperfusion. Control hearts (Con) received Krebs-Henseleit buffer as vehicle only. Pre- and postconditioning was achieved by administration of 11 mmol/L Mannitol for 10 min before ischemia (Man-PC) or immediately at the onset of reperfusion (Man-PoC), respectively. In further groups, the mK_ATP channel blocker 5HD, was applied with and without Mannitol, to determine the potential underlying cardioprotective mechanisms. Primary endpoint was infarct size, determined by triphenyltetrazolium chloride staining. Mannitol significantly reduced infarct size both as a pre- (Man-PC) and postconditioning (Man-PoC) stimulus compared to control hearts (Man-PC: 31 ± 4%; Man-PoC: 35 ± 6%, each p < 0.05 vs. Con: 57 ± 9%). The mK_ATP channel inhibitor completely abrogated the cardioprotective effect of Mannitol-induced pre- (5HD-PC-Man-PC: 59 ± 8%, p < 0.05 vs. Man-PC) and postconditioning (5HD-PoC-Man-PoC: 59 ± 10% vs. p < 0.05 Man-PoC). Infarct size was not influenced by 5HD itself (5HD-PC: 60 ± 14%; 5HD-PoC: 54 ± 14%, each ns vs. Con). This study demonstrates that Mannitol (1) induces myocardial pre- and postconditioning and (2) confers cardioprotection via activation of mK_ATP channels.

Keywords: mannitol; myocardial infarction; osmolarity; postconditioning; preconditioning.

MeSH terms

Animals
Cardiotonic Agents* / pharmacology
Diuretics, Osmotic / pharmacology
Ischemic Preconditioning, Myocardial* / methods
Male
Mannitol* / pharmacology
Myocardial Infarction* / drug therapy
Myocardial Infarction* / metabolism
Myocardial Infarction* / pathology
Myocardial Reperfusion Injury* / drug therapy
Myocardial Reperfusion Injury* / metabolism
Myocardial Reperfusion Injury* / pathology
Potassium Channels* / metabolism
Random Allocation
Rats
Rats, Wistar

Substances

Cardiotonic Agents
Diuretics, Osmotic
Mannitol
mitochondrial K(ATP) channel
Potassium Channels