Torregroza Carolin, Feige Katharina, Schneider Laura, Bunte Sebastian, Stroethoff Martin, Heinen André, Hollmann Markus W, Huhn Ragnar, Raupach Annika
Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
Department of Anesthesiology, Amsterdam University Medical Center (AUMC), Location AMC, Meiberdreef 9, 1105 AZ Amsterdam, The Netherlands.
J Clin Med. 2020 May 13;9(5):1445. doi: 10.3390/jcm9051445.
Pharmacological preconditioning (PC) and postconditioning (PoC), for example, by treatment with the α2-adrenoreceptor agonist Dexmedetomidine (Dex), protects hearts from ischemia-reperfusion (I/R) injury in experimental studies, however, translation into the clinical setting has been challenging. Acute hyperglycemia adversely affects the outcome of patients with myocardial infarction. Additionally, it also blocks cardioprotection by multiple pharmacological agents. Therefore, we investigated the possible influence of acute hyperglycemia on Dexmedetomidine-induced pre- and postconditioning. Experiments were performed on the hearts of male Wistar rats, which were randomized into 7 groups, placed in an isolated Langendorff system and perfused with Krebs-Henseleit buffer. All hearts underwent 33 min of global ischemia, followed by 60 min of reperfusion. Control (Con) hearts received Krebs-Henseleit buffer (Con KHB), glucose (Con HG) or mannitol (Con NG) as vehicle only. Hearts exposed to hyperglycemia (HG) received KHB, containing 11 mmol/L glucose (an elevated, but commonly used glucose concentration for Langendorff perfused hearts) resulting in a total concentration of 22 mmol/L glucose throughout the whole experiment. To ensure comparable osmolarity with HG conditions, normoglycemic (NG) hearts received mannitol in addition to KHB. Hearts were treated with 3 nM Dexmedetomidine (Dex) before (DexPC) or after ischemia (DexPoC), under hyperglycemic or normoglycemic conditions. Infarct size was determined by triphenyltetrazoliumchloride staining. Acute hyperglycemia had no impact on infarct size compared to the control group with KHB (Con HG: 56 ± 9% ns vs. Con KHB: 56 ± 7%). DexPC reduced infarct size despite elevated glucose levels (DexPC HG: 35 ± 3%, < 0.05 vs. Con HG). However, treatment with Dex during reperfusion showed no infarct size reduction under hyperglycemic conditions (DexPoC HG: 57 ± 9%, ns vs. Con HG). In contrast, hearts treated with mannitol demonstrated a significant decrease in infarct size compared to the control group (Con NG: 37 ± 3%, < 0.05 vs. Con KHB). The combination of Dex and mannitol presents exactly opposite results to hearts treated with hyperglycemia. While DexPC completely abrogates infarct reduction through mannitol treatment (DexPC NG: 55 ± 7%, < 0.05 vs. Con NG), DexPoC had no impact on mannitol-induced infarct size reduction (DexPoC NG: 38 ± 4%, ns vs. Con NG). Acute hyperglycemia inhibits DexPoC, while it has no impact on DexPC. Treatment with mannitol induces cardioprotection. Application of Dex during reperfusion does not influence mannitol-induced infarct size reduction, however, administering Dex before ischemia interferes with mannitol-induced cardioprotection.
例如，通过使用α2 - 肾上腺素能受体激动剂右美托咪定（Dex）进行药理学预处理（PC）和后处理（PoC），在实验研究中可保护心脏免受缺血再灌注（I/R）损伤，然而，将其转化到临床环境中却具有挑战性。急性高血糖会对心肌梗死患者的预后产生不利影响。此外，它还会阻断多种药物的心脏保护作用。因此，我们研究了急性高血糖对右美托咪定诱导的预处理和后处理的可能影响。实验在雄性Wistar大鼠的心脏上进行，将其随机分为7组，置于离体Langendorff系统中，并用Krebs - Henseleit缓冲液灌注。所有心脏均经历33分钟的全心缺血，随后再灌注60分钟。对照组（Con）心脏仅接受Krebs - Henseleit缓冲液（Con KHB）、葡萄糖（Con HG）或甘露醇（Con NG）作为溶媒。暴露于高血糖（HG）的心脏接受含有11 mmol/L葡萄糖的KHB（这是Langendorff灌注心脏常用的升高后的葡萄糖浓度），使得整个实验中葡萄糖总浓度达到22 mmol/L。为确保与HG条件下的渗透压相当，正常血糖（NG）组心脏除KHB外还接受甘露醇。在高血糖或正常血糖条件下，心脏在缺血前（DexPC）或缺血后（DexPoC）用3 nM右美托咪定（Dex）处理。通过三苯基四氮唑氯化物染色确定梗死面积。与接受KHB的对照组相比，急性高血糖对梗死面积无影响（Con HG：56 ± 9%，无显著差异 vs. Con KHB：56 ± 7%）。尽管葡萄糖水平升高，DexPC仍可减小梗死面积（DexPC HG：35 ± 3%，与Con HG相比，P < 0.05）。然而，在高血糖条件下，再灌注期间用Dex处理并未使梗死面积减小（DexPoC HG：57 ± 9%，与Con HG相比，无显著差异）。相比之下，用甘露醇处理的心脏与对照组相比梗死面积显著减小（Con NG：37 ± 3%，与Con KHB相比，P < 0.05）。Dex与甘露醇联合使用对心脏的作用与高血糖处理的心脏完全相反。虽然DexPC完全消除了通过甘露醇处理导致的梗死面积减小（DexPC NG：55 ± 7%，与Con NG相比，P < 0.05），但DexPoC对甘露醇诱导的梗死面积减小无影响（DexPoC NG：38 ± 4%，与Con NG相比，无显著差异）。急性高血糖抑制DexPoC，而对DexPC无影响。甘露醇处理可诱导心脏保护作用。再灌注期间应用Dex不影响甘露醇诱导的梗死面积减小，然而，缺血前给予Dex会干扰甘露醇诱导的心脏保护作用。
