格列美脲治疗可促进糖尿病心脏的缺血预适应。

Glimepiride treatment facilitates ischemic preconditioning in the diabetic heart.

机构信息

The Hatter Cardiovascular Institute, University College London Hospital and Medical School, London, UK.

出版信息

J Cardiovasc Pharmacol Ther. 2013 May;18(3):263-9. doi: 10.1177/1074248412468945. Epub 2012 Dec 21.

DOI:10.1177/1074248412468945

PMID:23263382

Abstract

AIMS

The diabetic heart is resistant to the myocardial infarct-limiting effects of ischemic preconditioning (IPC). This may be in part due to the downregulation of the phosphatidylinositol 3'-kinase-Akt pathway, an essential component of IPC protection. We hypothesized that treating the diabetic heart with the sulfonylurea, glimepiride, which has been reported to activate Akt, may lower the threshold required to protect the diabetic heart by IPC.

METHODS

Goto-Kakizaki rats (a type II lean model of diabetes) received glimepiride (20 mg/kg per d, by oral gavage) or vehicle for (a) 3 months (chronic treatment) or (b) 24 hours (subacute treatment). In the third group, glimepiride (10 μmol/L) was administered only to the isolated hearts on the Langendorff apparatus (acute treatment). All hearts were subjected to 35 minutes ischemia and 120 minutes reperfusion ex vivo, at the end of which infarct size was determined by tetrazolium staining. Preconditioning treatment comprised 1 (IPC-1) or 3 (IPC-3) cycles of 5 minutes global ischemia and 10 minutes reperfusion.

RESULTS

The diabetic heart was found to be resistant to IPC such that 3-IPC cycles, instead of the usual 1-IPC cycle, were required for cardioprotection. However, pretreatment with glimepiride lowered the threshold for IPC such that both 1 and 3 cycles of IPC elicited cardioprotection: chronic glimepiride treatment (IPC-1 31.9% ± 3.8% and IPC-3 33.5% ± 2.4% vs 43.9% ± 1.4% control, P < .05; N > 6 per group); subacute glimepiride treatment (IPC-1 31.1% ± 3.0% and IPC-3 29.3% ± 3.3% vs 42.2% ± 2.3% control, P < .05 N > 6 per group); and acute glimepiride treatment (IPC-1 28.2% ± 3.7% and IPC-3 24.6% ± 5.4% vs 41.9% ± 5.4% control, P < .05; N > 6 per group). This effect of glimepiride was independent of changes in blood glucose.

CONCLUSIONS

We report for the first time that glimepiride treatment facilitates the cardioprotective effect elicited by IPC in the diabetic heart.

摘要

目的

糖尿病心脏对缺血预处理（IPC）的心肌梗死限制作用具有抗性。这可能部分归因于磷脂酰肌醇 3'-激酶-Akt 途径的下调，这是 IPC 保护的一个重要组成部分。我们假设用磺酰脲类药物格列美脲治疗糖尿病心脏，格列美脲已被报道可激活 Akt，可能会降低通过 IPC 保护糖尿病心脏所需的阈值。

方法

Goto-Kakizaki 大鼠（II 型瘦素型糖尿病的一种模型）接受格列美脲（每天 20mg/kg，口服灌胃）或载体（a）3 个月（慢性治疗）或（b）24 小时（亚急性治疗）。在第三组中，仅在 Langendorff 仪器上给予格列美脲（10μmol/L）进行急性处理。所有心脏均在体外经历 35 分钟缺血和 120 分钟再灌注，最后通过四唑染色确定梗死面积。预处理包括 1（IPC-1）或 3（IPC-3）个 5 分钟的全缺血和 10 分钟的再灌注循环。

结果

发现糖尿病心脏对 IPC 具有抗性，以至于需要 3-IPC 循环而不是通常的 1-IPC 循环来进行心脏保护。然而，格列美脲预处理降低了 IPC 的阈值，使得 1 和 3 个 IPC 循环都能引起心脏保护：慢性格列美脲治疗（IPC-1 为 31.9%±3.8%和 IPC-3 为 33.5%±2.4%，而对照组为 43.9%±1.4%，P<.05；每组>6 只）；亚急性格列美脲治疗（IPC-1 为 31.1%±3.0%和 IPC-3 为 29.3%±3.3%，而对照组为 42.2%±2.3%，P<.05；每组>6 只）；和急性格列美脲治疗（IPC-1 为 28.2%±3.7%和 IPC-3 为 24.6%±5.4%，而对照组为 41.9%±5.4%，P<.05；每组>6 只）。格列美脲的这种作用独立于血糖变化。