Background: Cardioprotective strategies against ischemia-reperfusion injury (IRI) that remain effective in the clinical arena need to be developed. Therefore, maintained efficacy of cardioprotective strategies in the presence of drugs routinely used clinically (e.g., opiates, benzodiazepines, P2Y12 antagonist, propofol) need to be identified in preclinical models. Methods: Here, we examined the efficacy of promising cardioprotective compounds [fingolimod (Fingo), empagliflozin (Empa), melatonin (Mela) and nicotinamide riboside (NR)] administered i.v. as bolus before start ischemia. Infarct size as percentage of the area of risk (IS%) was determined following 25 min of left ascending coronary (LAD) ischemia and 2 h of reperfusion in a fentanyl-midazolam anesthetized IRI rat model. Plasma lactate dehydrogenase (LDH) activity at 30 min reperfusion was determined as secondary outcome parameter. Following pilot dose-response experiments of each compound (3 dosages, n = 4-6 animals per dosage), potential cardioprotective drugs at the optimal observed dosage were subsequently tested alone or in combination (n = 6-8 animals per group). The effective treatment was subsequently tested in the presence of a P2Y12 antagonist (cangrelor; n = 6/7) or propofol aesthesia (n = 6 both groups). Results: Pilot studies suggested potential cardioprotective effects for 50 mg/kg NR (p = 0.005) and 500 μg/kg melatonin (p = 0.12), but not for Empa or Fingo. Protection was subsequently tested in a new series of experiments for solvents, NR, Mela and NR+Mela. Results demonstrated that only singular NR was able to reduce IS% (30 ± 14 vs. 60 ± 16%, P = 0.009 vs. control). Mela (63 ± 18%) and NR+Mela (47 ± 15%) were unable to significantly decrease IS%. NR still reduced IS in the presence of cangrelor (51 ± 18 vs. 71 ± 4%, P = 0.016 vs. control), but lost protection in the presence of propofol anesthesia (62 ± 16 vs. 60 ± 14%, P = 0.839 vs. control). LDH activity measurements supported all IS% results. Conclusion: This observational study suggests that NR is a promising cardioprotective agent to target cardiac ischemia-reperfusion injury in clinical conditions employing opioid agonists, benzodiazepines and platelet P2Y12 inhibitors, but not propofol.

中文翻译：

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已知药物在临床相关条件下大鼠缺血再灌注模型中的心脏保护特性：只有 NAD 前体烟酰胺核苷在芬太尼、咪达唑仑和坎格雷洛存在的情况下减少梗塞面积，而丙泊酚则不然。

背景：需要开发在临床领域仍然有效的针对缺血再灌注损伤 (IRI) 的心脏保护策略。因此，需要在临床前模型中确定在临床常规使用的药物（例如，阿片类药物、苯二氮卓类药物、P2Y12 拮抗剂、丙泊酚）存在下心脏保护策略的有效性。方法：在这里，我们检查了有希望的心脏保护化合物 [芬戈莫德 (Fingo)、恩格列净 (Empa)、褪黑激素 (Mela) 和烟酰胺核苷 (NR)] 在缺血开始前静脉注射的功效。在芬太尼-咪达唑仑麻醉的 IRI 大鼠模型中，在左升冠状动脉 (LAD) 缺血 25 分钟和再灌注 2 小时后，确定梗死面积占风险面积的百分比 (IS%)。再灌注 30 分钟时的血浆乳酸脱氢酶 (LDH) 活性被确定为次要结果参数。在每种化合物的试点剂量反应实验（3 个剂量，每个剂量 n = 4-6 只动物）之后，随后单独或组合测试最佳观察剂量下的潜在心脏保护药物（每组 n = 6-8 只动物）。随后在存在 P2Y12 拮抗剂（坎格雷洛；n = 6/7）或异丙酚麻醉（两组 n = 6）的情况下测试了有效治疗。结果：初步研究表明，50 mg/kg NR (p = 0.005) 和 500 μg/kg 褪黑激素 (p = 0.12) 具有潜在的心脏保护作用，但对 Empa 或 Fingo 则没有。随后在溶剂、NR、Mela 和 NR+Mela 的一系列新实验中测试了保护作用。结果表明，只有单一的 NR 才能降低 IS%（30 ± 14 对 60 ± 16%，P = 0.009 与对照）。Mela (63 ± 18%) 和 NR + Mela (47 ± 15%) 无法显着降低 IS%。在存在坎格雷洛的情况下，NR 仍然降低 IS（51 ± 18 对 71 ± 4%，P = 0.016 对对照），但在丙泊酚麻醉的情况下失去保护（62 ± 16 对 60 ± 14%，P = 0.839 与对照）。LDH 活性测量支持所有 IS% 结果。结论：这项观察性研究表明，NR 是一种有前途的心脏保护剂，可在使用阿片类激动剂、苯二氮卓类和血小板 P2Y12 抑制剂的临床条件下靶向心脏缺血-再灌注损伤，但不是丙泊酚。但在丙泊酚麻醉的情况下失去保护（62 ± 16 vs. 60 ± 14%，P = 0.839 vs. control）。LDH 活性测量支持所有 IS% 结果。结论：这项观察性研究表明，NR 是一种有前途的心脏保护剂，可在使用阿片类激动剂、苯二氮卓类和血小板 P2Y12 抑制剂的临床条件下靶向心脏缺血-再灌注损伤，但不是丙泊酚。但在丙泊酚麻醉的情况下失去保护（62 ± 16 vs. 60 ± 14%，P = 0.839 vs. control）。LDH 活性测量支持所有 IS% 结果。结论：这项观察性研究表明，NR 是一种有前途的心脏保护剂，可在使用阿片类激动剂、苯二氮卓类和血小板 P2Y12 抑制剂的临床条件下靶向心脏缺血-再灌注损伤，但不是丙泊酚。