Laboratoty of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, Athens, Greece.
Institute for Vascular Signaling, Goethe University, Theodor Stern Kai 7, Frankfurt, Germany.
Cardiovasc Res. 2019 Mar 1;115(3):625-636. doi: 10.1093/cvr/cvy222.
Nitroglycerine (NTG) given prior to an ischaemic insult exerts cardioprotective effects. However, whether administration of an acute low dose of NTG in a clinically relevant manner following an ischaemic episode limits infarct size, has not yet been explored.
Adult mice were subjected to acute myocardial infarction in vivo and then treated with vehicle or low-dose NTG prior to reperfusion. This treatment regimen minimized myocardial infarct size without affecting haemodynamic parameters but the protective effect was absent in mice rendered tolerant to the drug. Mechanistically, NTG was shown to nitrosate and inhibit cyclophilin D (CypD), and NTG administration failed to limit infarct size in CypD knockout mice. Additional experiments revealed lack of the NTG protective effect following genetic (knockout mice) or pharmacological inhibition (L-NAME treatment) of the endothelial nitric oxide synthase (eNOS). The protective effect of NTG was attributed to preservation of the eNOS dimer. Moreover, NTG retained its cardioprotective effects in a model of endothelial dysfunction (ApoE knockout) by preserving CypD nitrosation. Human ischaemic heart biopsies revealed reduced eNOS activity and exhibited reduced CypD nitrosation.
Low-dose NTG given prior to reperfusion reduces myocardial infarct size by preserving eNOS function, and the subsequent eNOS-dependent S-nitrosation of CypD, inhibiting cardiomyocyte necrosis. This novel pharmacological action of NTG warrants confirmation in clinical studies, although our data in human biopsies provide promising preliminary results.
在缺血性损伤前给予硝化甘油（NTG）可发挥心脏保护作用。然而，在缺血性发作后以临床相关的方式给予急性低剂量 NTG 是否限制梗死面积，尚未得到探索。
成年小鼠在体内发生急性心肌梗死，然后在再灌注前用载体或低剂量 NTG 进行治疗。这种治疗方案最大限度地减少了心肌梗死面积，而不影响血液动力学参数，但在对药物耐受的小鼠中，保护作用不存在。从机制上讲，NTG 被证明可以亚硝化和抑制亲环蛋白 D（CypD），并且 NTG 给药不能限制 CypD 敲除小鼠的梗死面积。进一步的实验表明，在内皮型一氧化氮合酶（eNOS）的遗传（敲除小鼠）或药理学抑制（L-NAME 处理）后，NTG 没有保护作用。NTG 的保护作用归因于 eNOS 二聚体的保存。此外，NTG 通过保存 CypD 亚硝化，在内皮功能障碍（ApoE 敲除）模型中保留了其心脏保护作用。人类缺血性心脏活检显示 eNOS 活性降低，并表现出 CypD 亚硝化减少。
在再灌注前给予低剂量 NTG 可通过保存 eNOS 功能减少心肌梗死面积，随后 CypD 的 eNOS 依赖性 S-亚硝化抑制心肌细胞坏死。NTG 的这种新的药理学作用值得在临床研究中进一步确认，尽管我们在人类活检中的数据提供了有希望的初步结果。
