Influence of Hyperglycemia on Dexmedetomidine-Induced Cardioprotection in the Isolated Perfused Rat Heart

Abstract

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%, p < 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%, p < 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%, p < 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.

Exploring the role of neurogenic pathway-linked cholecystokinin release in remote preconditioning-induced cardioprotection

“…The isolated hearts were mounted on the Langendorff system and perfused with perfused with Kreb's Henseleit solution at 37°C. The inflow of physiological solution was stopped for 30 minutes to induce global ischemia and afterwards, the flow of KH was reinstituted for 120 minutes to establish reperfusion 18 , 19 .…”

Cardioprotective Properties of Mannitol—Involvement of Mitochondrial Potassium Channels

“…The respective Mannitol concentration of 11 mmol/L employed in this study was taken from the literature as well as one of our previous studies. In a preliminary experimental protocol, we investigated the influence of hyperglycemia on cardioprotection by Dexmedetomidine [ 42 ]. To ensure comparable osmolarity in all experiments, normoglycemic groups were treated with Mannitol—achieving the same osmolar conditions to hyperglycemia without affecting glucose levels.…”

“…All experiments were performed on male Wistar rats (2–3 months old), as described previously [ 42 ]. In short, animals were anesthetized with intraperitoneal injection of pentobarbital (80 mg/kg body weight, Narcoren, Merial, Germany) and decapitated.…”

“…Mannitol was applied in a concentration of 11 mmol/L as a preconditioning stimulus (PC) before or a postconditioning stimulus (PoC) after ischemia. This concentration of Mannitol was determined to induce significant infarct size reduction when applied permanently—throughout the entire experiment—in a previously performed study [ 42 ].…”

Pharmacological Conditioning of the Heart: An Update on Experimental Developments and Clinical Implications

“…In line with these results, our own research showed that preconditioning with dexmedetomidine confers cardioprotection despite the presence of acute hyperglycemia. Unfortunately, elevated glucose levels interfere with dexmedetomidine-induced postconditioning [ 90 ]. Additionally, in hearts with endothelial dysfunction, the protective effects of dexmedetomidine preconditioning are maintained [ 91 ].…”