|
|
右美托咪定对心脏缺血再灌注损伤的保护作用研究进展
|
Abstract:
右美托咪定(Dexmedetomidine, DEX)是一种高选择性的α2肾上腺素受体激动剂，该药物具有镇静镇痛、减轻应激及炎症反应及抗焦虑等多种作用，因此常用于手术围术期或重症监护病房机械通气时的辅助治疗。然而，动物实验研究和临床试验都已充分证实，右美托咪定也是一种抗缺血再灌注损伤(Ischemia-Reperfusion Injury, IRI)的心脏保护药物。本文深入总结了右美托咪定在抗心脏缺血再灌注损伤中的作用机制和信号通路；此外，本文综述了目前在心脏手术围术期中应用右美托咪定保护缺血心脏的临床研究，以期为未来的研究方向提供启示。我们希望这些研究成果不仅能够为心脏手术患者带来益处，还能拓展至更广泛的临床领域，如急性冠脉综合征患者，从而使更多患者受益。
Dexmedetomidine (DEX) is a highly selective α2 adrenergic receptor agonist known for its sedative and analgesic properties. It exhibits various effects including pain relief, anti-anxiety properties, and reduction of stress and inflammatory responses, making it a common adjunctive therapy during perioperative surgery and mechanical ventilation in intensive care units. Both animal experimental studies and clinical trials have demonstrated the cardioprotective potential of dexmedetomidine against ischemia-reperfusion injury (IRI). This review article aims to explore the mechanisms and signaling pathways underlying dexmedetomidine’s anti-cardiac IRI effects. Furthermore, it will provide an overview of the current use of dexmedetomidine during the perioperative period of cardiac surgery for cardiac protection and suggest potential future research directions. The findings from these studies are expected to not only benefit patients undergoing cardiac surgery, but also have implications for broader clinical applications, such as in patients with acute coronary syndrome, thereby extending the benefits to a larger patient population.
| [1] | Cakir, M., Polat, A., Tekin, S., Vardi, N., Taslidere, E., Rumeysa Duran, Z., et al. (2015) The Effect of Dexmedetomidine against Oxidative and Tubular Damage Induced by Renal Ischemia Reperfusion in Rats. Renal Failure, 37, 704-708. https://doi.org/10.3109/0886022x.2015.1011550 |
| [2] | Schmitz, J. and Holzgrabe, U. (2011) Die Entwicklung Selektiver α2-Rezeptor-Agonisten. Pharmazie in unserer Zeit, 40, 496-502. https://doi.org/10.1002/pauz.201100446 |
| [3] | 杨峰, 林成新. 右美托咪定心血管效应的机制[J]. 临床麻醉学杂志, 2021, 37(9): 999-1002. |
| [4] | 杨逸成, 陈贝儿, 叶凯雁, 等. 右美托咪定的心脏保护机制及其临床应用价值[J]. 中国医学科学院学报, 2022, 44(1): 130-135. |
| [5] | Roekaerts, P.M., Prinzen, F.W. and De Lange, S. (1996) Beneficial Effects of Dexmedetomidine on Ischaemic Myocardium of Anaesthetized Dogs. British Journal of Anaesthesia, 77, 427-429. https://doi.org/10.1093/bja/77.3.427 |
| [6] | 万军. 右美托咪定对冠心病患者围手术期心率和血压的影响[J]. 中国医学创新, 2014, 11(26): 47-49. |
| [7] | 张海媛. 右美托咪定不同给药方式用于妇科腹腔镜手术的临床麻醉效果比较[J]. 中国实用医药, 2020, 15(3): 141-142. |
| [8] | Kunisawa, T., Nagata, O., Nagashima, M., Mitamura, S., Ueno, M., Suzuki, A., et al. (2009) Dexmedetomidine Suppresses the Decrease in Blood Pressure during Anesthetic Induction and Blunts the Cardiovascular Response to Tracheal Intubation. Journal of Clinical Anesthesia, 21, 194-199. https://doi.org/10.1016/j.jclinane.2008.08.015 |
| [9] | Chrysostomou, C., Beerman, L., Shiderly, D., Berry, D., Morell, V.O. and Munoz, R. (2008) Dexmedetomidine: A Novel Drug for the Treatment of Atrial and Junctional Tachyarrhythmias during the Perioperative Period for Congenital Cardiac Surgery: A Preliminary Study. Anesthesia & Analgesia, 107, 1514-1522. https://doi.org/10.1213/ane.0b013e318186499c |
| [10] | Chrysostomou, C., Morell, V.O., Wearden, P., Sanchez-de-Toledo, J., Jooste, E.H. and Beerman, L. (2012) Dexmedetomidine: Therapeutic Use for the Termination of Reentrant Supraventricular Tachycardia. Congenital Heart Disease, 8, 48-56. https://doi.org/10.1111/j.1747-0803.2012.00669.x |
| [11] | 杨毅峰, 叶楠, 王琳, 等. 右美托咪定抗缺血再灌注损伤的信号通路[J]. 中国组织工程研究, 2024, 28(9): 1464-1469. |
| [12] | Ibacache, M., Sanchez, G., Pedrozo, Z., Galvez, F., Humeres, C., Echevarria, G., et al. (2012) Dexmedetomidine Preconditioning Activates Pro-Survival Kinases and Attenuates Regional Ischemia/Reperfusion Injury in Rat Heart. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, 1822, 537-545. https://doi.org/10.1016/j.bbadis.2011.12.013 |
| [13] | Rossello, X. and Yellon, D.M. (2017) The RISK Pathway and Beyond. Basic Research in Cardiology, 113, Article 2. https://doi.org/10.1007/s00395-017-0662-x |
| [14] | Chang, J., Jin, M. and Liu, J. (2020) Dexmedetomidine Pretreatment Protects the Heart Against Apoptosis in Ischemia/Reperfusion Injury in Diabetic Rats by Activating PI3K/Akt Signaling in Vivo and in Vitro. Biomedicine & Pharmacotherapy, 127, Article ID: 110188. https://doi.org/10.1016/j.biopha.2020.110188 |
| [15] | Zhang, J., Jiang, H., Liu, D.H., et al. (2019) Effects of Dexmedetomidine on Myocardial Ischemia-Reperfusion Injury through PI3K-Akt-mTOR Signaling Pathway. European Review for Medical and Pharmacological Sciences, 23, 6736-6743. |
| [16] | Song, J., Du, J., Tan, X., Wu, Z., Yuan, J. and Cong, B. (2021) Dexmedetomidine Protects the Heart against Ischemia Reperfusion Injury via Regulation of the Bradykinin Receptors. European Journal of Pharmacology, 911, Article ID: 174493. https://doi.org/10.1016/j.ejphar.2021.174493 |
| [17] | Zhang, J., Peng, K., Zhang, J., Meng, X. and Ji, F. (2017) Dexmedetomidine Preconditioning May Attenuate Myocardial Ischemia/Reperfusion Injury by Down-Regulating the HMGB1-TLR4-MyD88-NF-кB Signaling Pathway. PLOS ONE, 12, e0172006. https://doi.org/10.1371/journal.pone.0172006 |
| [18] | Zhang, J., Xia, F., Zhao, H., Peng, K., Liu, H., Meng, X., et al. (2019) Dexmedetomidine-Induced Cardioprotection Is Mediated by Inhibition of High Mobility Group Box-1 and the Cholinergic Anti-Inflammatory Pathway in Myocardial Ischemia-Reperfusion Injury. PLOS ONE, 14, e0218726. https://doi.org/10.1371/journal.pone.0218726 |
| [19] | Hu, X., li, J., Fu, M., Zhao, X. and Wang, W. (2021) The JAK/STAT Signaling Pathway: From Bench to Clinic. Signal Transduction and Targeted Therapy, 6, Article No. 402. https://doi.org/10.1038/s41392-021-00791-1 |
| [20] | Chen, Z., Hong, Y., Wen, S., Zhan, Y. and Huang, W. (2023) Dexmedetomidine Pretreatment Protects against Myocardial Ischemia/Reperfusion Injury by Activating STAT3 Signaling. Anesthesia & Analgesia, 137, 426-439. https://doi.org/10.1213/ane.0000000000006487 |
| [21] | 张晓秀, 吴海鹰, 王艳雪, 等. 右美托咪定激活Nrf2-ARE信号通路对创伤性脑损伤的抗氧化作用[J]. 中华重症医学电子杂志(网络版), 2018, 4(2): 176-181. |
| [22] | Li, H., Wang, T., Wu, L., Xue, F., Zhang, G. and Yan, T. (2022) Role of Keap1-Nrf2/Are Signal Transduction Pathway in Protection of Dexmedetomidine Preconditioning against Myocardial Ischemia/Reperfusion Injury. Bioscience Reports, 42, BSR20221306. https://doi.org/10.1042/bsr20221306 |
| [23] | Han, H., Dai, D., Hu, J., Zhu, J., Lu, L., Tao, G., et al. (2019) Dexmedetomidine Improves Cardiac Function and Protects against Maladaptive Remodeling Following Myocardial Infarction. Molecular Medicine Reports, 20, 5183-5189. https://doi.org/10.3892/mmr.2019.10774. |
| [24] | Wu, Z., Davis, J.R.J. and Zhu, Y. (2020) Dexmedetomidine Protects against Myocardial Ischemia/Reperfusion Injury by Ameliorating Oxidative Stress and Cell Apoptosis through the Trx1-Dependent Akt Pathway. BioMed Research International, 2020, Article ID: 8979270. https://doi.org/10.1155/2020/8979270 |
| [25] | Riquelme, J.A., Westermeier, F., Hall, A.R., Vicencio, J.M., Pedrozo, Z., Ibacache, M., et al. (2016) Dexmedetomidine Protects the Heart against Ischemia-Reperfusion Injury by an Endothelial eNOS/NO Dependent Mechanism. Pharmacological Research, 103, 318-327. https://doi.org/10.1016/j.phrs.2015.11.004 |
| [26] | Yoshikawa, Y., Hirata, N., Kawaguchi, R., Tokinaga, Y. and Yamakage, M. (2018) Dexmedetomidine Maintains Its Direct Cardioprotective Effect against Ischemia/Reperfusion Injury in Hypertensive Hypertrophied Myocardium. Anesthesia & Analgesia, 126, 443-452. https://doi.org/10.1213/ane.0000000000002452 |
| [27] | Wang, M., Pan, W., Xu, Y., Zhang, J., Wan, J. and Jiang, H. (2022) Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases. Journal of Inflammation Research, 15, 3083-3094. https://doi.org/10.2147/jir.s350109 |
| [28] | 丁允莹, 嵇富海, 彭科. 右美托咪定的器官保护作用及其机制概述[J]. 解放军医学杂志, 2023, 48(11): 1267-1275. |
| [29] | Ramkiran, S. (2015) BIS Targeted Propofol Sparing Effects of Dexmedetomidine versus Ketamine in Outpatient ERCP: A Prospective Randomised Controlled Trial. Journal of Clinical and Diagnostic Research, 9, UC07-UC12. https://doi.org/10.7860/jcdr/2015/12435.5991 9(5):Uc07-12. |
| [30] | Kimura, M., Ichimura, S., Sasaki, K., Masuya, H., Suzuki, T., Wakana, S., et al. (2015) Endoplasmic Reticulum Stress-Mediated Apoptosis Contributes to a Skeletal Dysplasia Resembling Platyspondylic Lethal Skeletal Dysplasia, Torrance Type, in a Novel Col2a1 Mutant Mouse Line. Biochemical and Biophysical Research Communications, 468, 86-91. https://doi.org/10.1016/j.bbrc.2015.10.160 |
| [31] | Yang, Y., Wang, H., Song, N., Jiang, Y., Zhang, J., Meng, X., et al. (2021) Dexmedetomidine Attenuates Ischemia/Reperfusion-Induced Myocardial Inflammation and Apoptosis through Inhibiting Endoplasmic Reticulum Stress Signaling. Journal of Inflammation Research, 14, 1217-1233. https://doi.org/10.2147/jir.s292263 |
| [32] | ？íha, H., Kotulák, T., B？ezina, A., Hess, L., Kramá？, P., Szárszoi, O., et al. (2012) Comparison of the Effects of Ketamine-Dexmedetomidine and Sevoflurane-Sufentanil Anesthesia on Cardiac Biomarkers after Cardiac Surgery: An Observational Study. Physiological Research, 61, 63-72. https://doi.org/10.33549/physiolres.932224 |
| [33] | Wang, D., Lin, Q., Du, M., Zheng, G., Xu, W., Zhang, H., et al. (2020) Protective Effect of Dexmedetomidine on Perioperative Myocardial Injury in Patients With Stanford Type-a Aortic Dissection. Revista da Associa？？o Médica Brasileira, 66, 1638-1644. https://doi.org/10.1590/1806-9282.66.12.1638 |
| [34] | Wang, L., Wang, S., Xing, Z., Li, F., Teng, J. and Jia, T. (2020) Application of Dexmedetomidine in Cardiopulmonary Bypass Prefilling. Dose-Response, 18. https://doi.org/10.1177/1559325820939764 |
| [35] | Elgebaly, A., Fathy, S., Sallam, A. and Elbarbary, Y. (2020) Cardioprotective Effects of Propofol-Dexmedetomidine in Open-Heart Surgery: A Prospective Double-Blind Study. Annals of Cardiac Anaesthesia, 23, 134-141. https://doi.org/10.4103/aca.aca_168_18 |
| [36] | Ueki, M., Kawasaki, T., Habe, K., Hamada, K., Kawasaki, C. and Sata, T. (2014) The Effects of Dexmedetomidine on Inflammatory Mediators after Cardiopulmonary Bypass. Anaesthesia, 69, 693-700. https://doi.org/10.1111/anae.12636 |
| [37] | Torregroza, C., Feige, K., Schneider, L., Bunte, S., Stroethoff, M., Heinen, A., et al. (2020) Influence of Hyperglycemia on Dexmedetomidine-Induced Cardioprotection in the Isolated Perfused Rat Heart. Journal of Clinical Medicine, 9, Article 1445. https://doi.org/10.3390/jcm9051445 |
