右美托咪定的心肌保护作用机制研究进展
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摘要
右美托咪定(DEX)作为一种高选择性的α_2肾上腺素受体激动剂,被广泛用于重症监护病房和手术室内镇静;α_2肾上腺素受体是一种广泛分布于机体的G蛋白偶联受体,其激活对调控细胞间信号转导、离子通道开放、炎症介质的产生均有明显作用。DEX具有抗氧化应激、减轻炎症反应、改善组织微循环、抑制细胞凋亡、抑制交感神经活性、保护线粒体结构和功能等作用,并对脏器的缺血再灌注损伤表现出明显的保护作用。虽然DEX的心肌保护作用是当前的研究热点,但其具体作用机制仍存在争议,未来需深入研究,以更好地应用于临床。
Dexmedetomidine( DEX),a highly selective α_2 adrenergic receptor agonist,is widely used in intensive care unit and operation room for sedation. The α_2 adrenergic receptor is a G protein-coupled receptor widely distributed in the body. Its activation plays an important role in regulating intercellular signal transduction,ion channel opening and inflammatory mediator production. DEX has the effects of anti-oxidative stress,reducing inflammatory reaction,inhibition of apoptosis,improvement of microcirculation,inhibition of sympathetic activity,protection of mitochondrial structure and function,and obviously protective effects on organ ischemia-reperfusion injury. Although the cardioprotective effect of DEX is currently a research hotspot,its specific mechanism remains controversial,and further research is needed in the future to make it better applied in the clinical practice.
Dexmedetomidine( DEX),a highly selective α_2 adrenergic receptor agonist,is widely used in intensive care unit and operation room for sedation. The α_2 adrenergic receptor is a G protein-coupled receptor widely distributed in the body. Its activation plays an important role in regulating intercellular signal transduction,ion channel opening and inflammatory mediator production. DEX has the effects of anti-oxidative stress,reducing inflammatory reaction,inhibition of apoptosis,improvement of microcirculation,inhibition of sympathetic activity,protection of mitochondrial structure and function,and obviously protective effects on organ ischemia-reperfusion injury. Although the cardioprotective effect of DEX is currently a research hotspot,its specific mechanism remains controversial,and further research is needed in the future to make it better applied in the clinical practice.
引文
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[11] Ren J,Li C,Liu Y,et al. Protective effect of dexmedetomidine against myocardial ischemia-reperfusion injury in rabbits[J].Acta Cir Bras,2018,33(1):22-30.
[12] Sun Y,Jiang C,Jiang J,et al. Dexmedetomidine protects mice against myocardium ischaemic/reperfusion injury by activating an AMPK/PI3K/Akt/e NOS pathway[J]. Clin Exp Pharmacol Physiol,2017,44(9):946-953.
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[15]杜英杰.右美托咪定的心脏保护作用[J].中国分子心脏病学杂志,2012,12(5):313-316.
[16] Yoshitomi O,Cho S,Hara T,et al. Direct protective effects of dexmedetomidine against myocardial ischemia-reperfusion injury in anesthetized pigs[J]. Shock,2012,38(1):92-97.
[17] Xu Y,Liu B,Zweier JL,et al. Formation of hydrogen peroxide and reduction of peroxynitrite via dismutation of superoxide at reperfusion enhances myocardial blood flow and oxygen consumption in postischemic mouse heart[J]. J Pharmacol Exp Ther,2008,327(2):402-410.
[18] Hazini A,Cemek M,Isildak I,et al. Investigation of ischemia modified albumin,oxidant and antioxidant markers in acute myocardial infarction[J]. Postepy Kardiol Interwencyjnej,2015,11(4):298-303.
[19] Stanger O,Aigner I,Schimetta W,et al. Antioxidant supplementation attenuates oxidative stress in patients undergoing coronary artery bypass graft surgery[J]. Tohoku J Exp Med,2014,232(2):145-154.
[20] Dhalla NS,Elmoselhi AB,Hata T,et al. Status of myocardial antioxidants in ischemia-reperfusion injury[J]. Cardiovasc Res,2000,47(3):446-456.
[21]蒋丽丽,齐择优,李李,等.盐酸右美托咪定对H2O2诱导的肺泡巨噬细胞氧化应激的影响[J].中南大学学报(医学版),2013,38(10):1014-1019.
[22]沈金美,李李,蒋丽丽,等.盐酸右美托咪定对H2O2诱导的库普弗细胞氧化应激和炎性反应的影响[J].中南大学学报(医学版),2016,41(5):477-481.
[23] Guler L,Bozkirli F,Bedirli N,et al. Comparison of the effects of dexmedetomidine vs. Ketamine in cardiac ischemia/reperfusion injury in rats-preliminary study[J]. Adv Clin Exp Med,2014,23(5):683-689.
[24] Wang H,Zhang S,Xu S,et al. The efficacy and mechanism of dexmedetomidine in myocardial apoptosis via the renin-angiotensinaldosterone system[J]. J Renin Angiotensin Aldosterone Syst,2015,16(4):1274-1280.
[25] Riquelme JA,Westermeier F,Hall AR,et al. Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial e NOS/NO dependent mechanism[J]. Pharmacol Res,2016,103:318-327.
[26] Cheng XY,Gu XY,Gao Q,et al. Effects of dexmedetomidine postconditioning on myocardial ischemia and the role of the PI3K/Akt-dependent signaling pathway in reperfusion injury[J]. Mol Med Rep,2016,14(1):797-803.
[27] Liu XR,Li T,Cao L,et al. Dexmedetomidine attenuates H2O2-induced neonatal rat cardiomyocytes apoptosis through mitochondria-and ER-medicated oxidative stress pathways[J]. Mol Med Rep,2018,17(5):7258-7264.
[28] Christia P,Frangogiannis NG. Targeting inflammatory pathways in myocardial infarction[J]. Eur J Clin Invest,2013,43(9):986-995.
[29] Frangogiannis NG. The inflammatory response in myocardial injury,repair,and remodelling[J]. Nat Rev Cardiol,2014,11(5):255-265.
[30] Yang D,Hong JH. Dexmedetomidine modulates histamine-induced Ca2+signaling and pro-inflammatory cytokine expre-ssion[J].Korean J Physiol harmacol,2015,19(5):413-420.
[31] Chen SL,Zhou W,Hua FZ,et al. In vitro effect of dexmedetomidine on the respiratory burst of neutrophils[J]. Genet Mol Res,2016,15(2):112-114.
[32]张静静,嵇富海,孟晓文,等.右美托咪定对大鼠心肌缺血再灌注时炎性反应的影响[J].中华麻醉学杂志,2016,36(5):633-634.
[33] Yang YF,Peng K,Liu H,et al. Dexmedetomidine preconditioning for myocardial protection in ischaemia-reperfusion injury in rats by downregulation of the high mobility group box 1-Toll-like receptor 4-nuclear factor kappaB signalling pathway[J]. Clin Exp Pharmacol Physiol,2017,44(3):353-361.
[34] Bulow NM,Colpo E,Pereira RP,et al. Dexmedetomidine decreases the inflammatory response to myocardial surgery under minicardiopulmonary bypass[J]. Braz J Med Biol Res,2016,49(4):e4646.
[35] Kitakaze M,Hori M,Gotoh K,et al. Beneficial effects of alpha 2-adrenoceptor activity on ischemic myocardium during coronary hypoperfusion in dogs[J]. Circ Res,1989,65(6):1632-1645.
[36] Ozturk L,Arslan M,Comu FM. The effects of low-high doses of dexmedetomidine on erythrocyte deformability in rats[J]. Bratisl Lek Listy,2012,113(6):347-349.
[37]吴财能,马武华,屠伟峰,等.右美托咪定对大鼠烫伤后心肌损伤的影响[J].广东医学,2012,33(8):1050-1052.
[38] Lawrence CJ,Prinzen FW,de Lange S. The effect of dexmedetomidine on nutrient organ blood flow[J]. Anesth Analg,1996,83(6):1160-1165.
[39] Zhou SZ,Li ZM,Liu XR,et al. Bidirectional regulatory effects of dexmedetomidine on porcine coronary tone in vitro[J]. Med Sci Monit,2017,23:1621-1626.
[40] Kalisnik J M,Avbelj V,Trobec R,et al. Assessment of cardiac autonomic regulation and ventricular repolarization after off-pump coronary artery bypass grafting[J]. Heart Surg Forum,2006,9(3):E661-667.
[41] Kalman JM,Munawar M,Howes LG,et al. Atrial fibrillation after coronary artery bypass grafting is associated with sympathetic activation[J]. Ann Thorac Surg,1995,60(6):1709-1715.
[42] Ren J,Zhang H,Huang L,et al. Protective effect of dexmedetomidine in coronary artery bypass grafting surgery[J]. Exp Ther Med,2013,6(2):497-502.
[43] Kunisawa T,Nagata O,Nagashima M,et al. Dexmedetomidine suppresses the decrease in blood pressure during anesthetic induction and blunts the cardiovascular response to tracheal intubation[J]. J Clin Anesth,2009,21(3):194-199.
[44]凌云志,孙瑗,梁启胜,等.右美托咪定对小儿心脏手术麻醉中血流动力学及应激反应的影响[J].上海医学,2012,35(2):96-100.
[45]方文倩,吕国义.右美托咪啶后处理对大鼠离体心脏缺血再灌注时线粒体损伤的影响[J].中华麻醉学杂志,2011,31(11):1394-1396.
[2] Cai Y,Xu H,Yan J,et al. Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury[J]. Mol Med Rep,2014,9(5):1542-1550.
[3] Hashemian M,Ahmadinejad M,Mohajerani SA,et al. Impact of dexmedetomidine on hemodynamic changes during and after coronary artery bypass grafting[J]. Ann Card Anaesth,2017,20(2):152-157.
[4] Aguilera IM,Vaughan RS. Calcium and the anaesthetist[J].Anaesthesia,2000,55(8):779-790.
[5] Stenger M,Fabrin A,Schmidt H,et al. High thoracic epidural analgesia as an adjunct to general anesthesia is associated with better outcome in low-to-moderate risk cardiac surgery patients[J].J Cardiothorac Vasc Anesth,2013,27(6):1301-1309.
[6] Huang S,Peng W,Yang N,et al. Myocardial injury in elderly patients after abdominal surgery[J]. Aging Clin Exp Res,2018,30(10):1217-1223.
[7] Sessler DI,Khanna AK. Perioperative myocardial injury and the contribution of hypotension[J]. Intensive Care Med,2018,44(6):811-822.
[8] Chun TT,Garcia-Toca M,Eng JF,et al. Postoperative infections are associated with increased risk of cardiac events in vascular patients[J]. Ann Vasc Surg,2017,41:151-159.
[9] Mauermann E,Puelacher C,Lurati BG. Myocardial injury after noncardiac surgery:An underappreciated problem and current challenges[J]. Curr Opin Anaesthesiol,2016,29(3):403-412.
[10]刘秀华,唐朝枢.缺血再灌注损伤的防治———从实验室到临床[J].中华心血管病杂志,2006,34(8):677-679.
[11] Ren J,Li C,Liu Y,et al. Protective effect of dexmedetomidine against myocardial ischemia-reperfusion injury in rabbits[J].Acta Cir Bras,2018,33(1):22-30.
[12] Sun Y,Jiang C,Jiang J,et al. Dexmedetomidine protects mice against myocardium ischaemic/reperfusion injury by activating an AMPK/PI3K/Akt/e NOS pathway[J]. Clin Exp Pharmacol Physiol,2017,44(9):946-953.
[13]陆沁源,邵东华.右美托咪定预处理对缺血再灌注损伤大鼠心肌线粒体功能的影响[J].南京医科大学学报(自然科学版),2016,36(10):1198-1201.
[14] Gyires K,Zadori ZS,Torok T,et al. alpha(2)-Adrenoceptor subtypes-mediated physiological,pharmacological actions[J]. Neurochem Int,2009,55(7):447-453.
[15]杜英杰.右美托咪定的心脏保护作用[J].中国分子心脏病学杂志,2012,12(5):313-316.
[16] Yoshitomi O,Cho S,Hara T,et al. Direct protective effects of dexmedetomidine against myocardial ischemia-reperfusion injury in anesthetized pigs[J]. Shock,2012,38(1):92-97.
[17] Xu Y,Liu B,Zweier JL,et al. Formation of hydrogen peroxide and reduction of peroxynitrite via dismutation of superoxide at reperfusion enhances myocardial blood flow and oxygen consumption in postischemic mouse heart[J]. J Pharmacol Exp Ther,2008,327(2):402-410.
[18] Hazini A,Cemek M,Isildak I,et al. Investigation of ischemia modified albumin,oxidant and antioxidant markers in acute myocardial infarction[J]. Postepy Kardiol Interwencyjnej,2015,11(4):298-303.
[19] Stanger O,Aigner I,Schimetta W,et al. Antioxidant supplementation attenuates oxidative stress in patients undergoing coronary artery bypass graft surgery[J]. Tohoku J Exp Med,2014,232(2):145-154.
[20] Dhalla NS,Elmoselhi AB,Hata T,et al. Status of myocardial antioxidants in ischemia-reperfusion injury[J]. Cardiovasc Res,2000,47(3):446-456.
[21]蒋丽丽,齐择优,李李,等.盐酸右美托咪定对H2O2诱导的肺泡巨噬细胞氧化应激的影响[J].中南大学学报(医学版),2013,38(10):1014-1019.
[22]沈金美,李李,蒋丽丽,等.盐酸右美托咪定对H2O2诱导的库普弗细胞氧化应激和炎性反应的影响[J].中南大学学报(医学版),2016,41(5):477-481.
[23] Guler L,Bozkirli F,Bedirli N,et al. Comparison of the effects of dexmedetomidine vs. Ketamine in cardiac ischemia/reperfusion injury in rats-preliminary study[J]. Adv Clin Exp Med,2014,23(5):683-689.
[24] Wang H,Zhang S,Xu S,et al. The efficacy and mechanism of dexmedetomidine in myocardial apoptosis via the renin-angiotensinaldosterone system[J]. J Renin Angiotensin Aldosterone Syst,2015,16(4):1274-1280.
[25] Riquelme JA,Westermeier F,Hall AR,et al. Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial e NOS/NO dependent mechanism[J]. Pharmacol Res,2016,103:318-327.
[26] Cheng XY,Gu XY,Gao Q,et al. Effects of dexmedetomidine postconditioning on myocardial ischemia and the role of the PI3K/Akt-dependent signaling pathway in reperfusion injury[J]. Mol Med Rep,2016,14(1):797-803.
[27] Liu XR,Li T,Cao L,et al. Dexmedetomidine attenuates H2O2-induced neonatal rat cardiomyocytes apoptosis through mitochondria-and ER-medicated oxidative stress pathways[J]. Mol Med Rep,2018,17(5):7258-7264.
[28] Christia P,Frangogiannis NG. Targeting inflammatory pathways in myocardial infarction[J]. Eur J Clin Invest,2013,43(9):986-995.
[29] Frangogiannis NG. The inflammatory response in myocardial injury,repair,and remodelling[J]. Nat Rev Cardiol,2014,11(5):255-265.
[30] Yang D,Hong JH. Dexmedetomidine modulates histamine-induced Ca2+signaling and pro-inflammatory cytokine expre-ssion[J].Korean J Physiol harmacol,2015,19(5):413-420.
[31] Chen SL,Zhou W,Hua FZ,et al. In vitro effect of dexmedetomidine on the respiratory burst of neutrophils[J]. Genet Mol Res,2016,15(2):112-114.
[32]张静静,嵇富海,孟晓文,等.右美托咪定对大鼠心肌缺血再灌注时炎性反应的影响[J].中华麻醉学杂志,2016,36(5):633-634.
[33] Yang YF,Peng K,Liu H,et al. Dexmedetomidine preconditioning for myocardial protection in ischaemia-reperfusion injury in rats by downregulation of the high mobility group box 1-Toll-like receptor 4-nuclear factor kappaB signalling pathway[J]. Clin Exp Pharmacol Physiol,2017,44(3):353-361.
[34] Bulow NM,Colpo E,Pereira RP,et al. Dexmedetomidine decreases the inflammatory response to myocardial surgery under minicardiopulmonary bypass[J]. Braz J Med Biol Res,2016,49(4):e4646.
[35] Kitakaze M,Hori M,Gotoh K,et al. Beneficial effects of alpha 2-adrenoceptor activity on ischemic myocardium during coronary hypoperfusion in dogs[J]. Circ Res,1989,65(6):1632-1645.
[36] Ozturk L,Arslan M,Comu FM. The effects of low-high doses of dexmedetomidine on erythrocyte deformability in rats[J]. Bratisl Lek Listy,2012,113(6):347-349.
[37]吴财能,马武华,屠伟峰,等.右美托咪定对大鼠烫伤后心肌损伤的影响[J].广东医学,2012,33(8):1050-1052.
[38] Lawrence CJ,Prinzen FW,de Lange S. The effect of dexmedetomidine on nutrient organ blood flow[J]. Anesth Analg,1996,83(6):1160-1165.
[39] Zhou SZ,Li ZM,Liu XR,et al. Bidirectional regulatory effects of dexmedetomidine on porcine coronary tone in vitro[J]. Med Sci Monit,2017,23:1621-1626.
[40] Kalisnik J M,Avbelj V,Trobec R,et al. Assessment of cardiac autonomic regulation and ventricular repolarization after off-pump coronary artery bypass grafting[J]. Heart Surg Forum,2006,9(3):E661-667.
[41] Kalman JM,Munawar M,Howes LG,et al. Atrial fibrillation after coronary artery bypass grafting is associated with sympathetic activation[J]. Ann Thorac Surg,1995,60(6):1709-1715.
[42] Ren J,Zhang H,Huang L,et al. Protective effect of dexmedetomidine in coronary artery bypass grafting surgery[J]. Exp Ther Med,2013,6(2):497-502.
[43] Kunisawa T,Nagata O,Nagashima M,et al. Dexmedetomidine suppresses the decrease in blood pressure during anesthetic induction and blunts the cardiovascular response to tracheal intubation[J]. J Clin Anesth,2009,21(3):194-199.
[44]凌云志,孙瑗,梁启胜,等.右美托咪定对小儿心脏手术麻醉中血流动力学及应激反应的影响[J].上海医学,2012,35(2):96-100.
[45]方文倩,吕国义.右美托咪啶后处理对大鼠离体心脏缺血再灌注时线粒体损伤的影响[J].中华麻醉学杂志,2011,31(11):1394-1396.