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 (mKATP) 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 mKATP 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 mKATP 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 mKATP channels.
Highlights
Introduction conditions of the Creative CommonsIschemic conditioning still remains a strong measure to confer cardioprotection by inducing infarct size reduction and thereby protecting the heart against the detrimental consequences of ischemia and reperfusion (I/R) injury [1]
Mannitol induces cardioprotection by pre- and/or postconditioning and (2) this effect is mediated via activation of mKATP channels
Our findings demonstrate for the first time, that mKATP are involved in the cardioprotective effect by Mannitol, as the mKATP channel inhibitor 5HD completely abolished infarct size reduction by Mannitol
Summary
Introduction conditions of the Creative CommonsIschemic conditioning still remains a strong measure to confer cardioprotection by inducing infarct size reduction and thereby protecting the heart against the detrimental consequences of ischemia and reperfusion (I/R) injury [1]. Invasiveness in the majority of cases, it is unattainable in daily clinical routine For this reason, pharmacological preconditioning (PC) and postconditioning (PoC) induced by treatment with various different substances, e.g., Dexmedetomidine, volatile anesthetics or opioids, gained importance over the years and have revealed persuading results comparable to ischemic conditioning [2,3]. 6-carbon natural alditol, is a hyperosmolar solution and osmotherapeutic agent only scarcely metabolized and mainly excreted rapidly via the kidneys [4] To this day, it is widely used in many fields of medicine due to its beneficial effects on the kidney [5], brain [6,7,8] and heart [4,9]. To its favorable effects on cerebral and renal function, Mannitol has been extensively used in cardiac surgery achieving an increased coronary blood flow, cardiac output, mean systemic arterial pressure, left-ventricular end-diastolic pressure and myocardial left-ventricular contractility [4]
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