5-羟色胺受体拮抗剂在肺动脉高压防治中的应用与展望

摘要/Abstract

摘要： 肺动脉高压是一组由多种病因和发病机制引起的以肺血管阻力进行性增加为特征的病理生理综合征。临床表现为右心室功能不全,预后不良,严重者可发生右心衰竭而死亡。本文主要综述了5-羟色胺与肺动脉高压的关系及5-羟色胺受体拮抗剂在肺动脉高压防治中的作用,展望了5-羟色胺受体拮抗剂可能是一类有潜力的新型治疗肺动脉高压的药物。

关键词: 5-羟色胺, 5-羟色胺受体, 拮抗剂, 肺动脉高压

Abstract: Pulmonary hypertension is a group of clinical pathophysiological syndrome characterized by increased pulmonary vascular resistance due to multiple etiologies and pathogenesis. The main clinical manifestations are right ventricular dysfunction with poor prognosis, and patient of severe right heart failure can even cause death. This article reviews the relationship between the 5-HT and pulmonary hypertension, and the 5-HT receptor antagonists' effects on the prevention and treatment of pulmonary hypertension. The article also prospects that 5-HT receptor antagonists may be a kind of very promising new drugs in the treatment of pulmonary hypertension.

Key words: 5-hydroxytryptamine, 5-hydroxytryptamine receptor, Antagonist, Pulmonary artery hypertension , , , ,

中图分类号:

R543.2

肖雄, 侯颖, 李小强. 5-羟色胺受体拮抗剂在肺动脉高压防治中的应用与展望[J]. 中国临床药理学与治疗学, 2011, 16(1): 111-115.

XIAO Xiong, HOU Ying, LI Xiao-qiang. Application and prospects of 5-HT receptor antagonists in the prevention and treatment of pulmonary hypertension[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2011, 16(1): 111-115.

参考文献

[1] 王虹,解卫平,汪海,等.盐酸埃他卡林对内皮素-1诱导的大鼠肺动脉高压的影响[J]. 中国临床药理学与治疗学, 2005,10(1):9-14.
[2] McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association[J]. Circulation, 2009,119(16):2250-2294.
[3] Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT) [J]. Eur Heart J, 2009, 30(20):2493- 2537.
[4] Liu C, Liu K, Ji Z, et al. Treatments for pulmonary arterial hypertension[J]. Respir Med, 2006, 100(5):765-774.
[5] Dwyer N, Kilpatrick D. Bosentan for the treatment of adult pulmonary hypertension[J]. Future Cardiol, 2011,7(1):19-37.
[6] Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension[J]. J Mol Cell Cardiol, 2008, 44(1):14-30.
[7] Nebigil CG, Etienne N, Schaerlinger B, et al. Developmentally regulated serotonin 5-HT2B receptors[J]. Int J Dev Neurosci, 2001, 19(4):365-372.
[8] Lederer DJ, Horn EM, Rosenzweig EB, et al. Plasma serotonin levels are normal in pulmonary arterial hypertension[J]. Pulm Pharmacol Ther, 2008, 21(1):112-114.
[9] Kereveur A, Callebert J, Humbert M, et al. High plasma serotonin levels in primary pulmonary hypertension. Effect of long-term epoprostenol (prostacyclin) therapy[J]. Arterioscler Thromb Vasc Biol, 2000, 20(10):2233-2239.
[10]Lam DD, Przydzial MJ, Ridley SH, et al. Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors[J]. Endocrinology,2008, 149(3):1323-1328.
[11]Hoyer D, Clarke DE, Fozard JR, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin) [J]. Pharmacol Rev, 1994, 46(2):157-203.
[12]MacLean MR. Endothelin-1 and serotonin: mediators of primary and secondary pulmonary hypertension[J]? J Lab Clin Med, 1999, 134(2):105-114.
[13]Rothman RB, Redmon JB, Raatz SK, et al. Chronic treatment with phentermine combined with fenfluramine lowers plasma serotonin[J]. Am J Cardiol, 2000, 85(7):913-915, A10.
[14]Rhodes CJ, Davidson A, Gibbs JS, et al. Therapeutic targets in pulmonary arterial hypertension[J]. Pharmacol Ther, 2009, 121(1):69-88.
[15]Glusa E, Pertz HH. Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT(2B) receptors[J]. Br J Pharmacol, 2000, 130(3):692-698.
[16]Watts SW. The development of enhanced arterial serotonergic hyperresponsiveness in mineralocorticoid hypertension[J]. J Hypertens, 1998, 16(6):811-822.
[17]Watts SW, Baez M, Webb RC. The 5-hydroxytryptamine2B receptor and 5-HT receptor signal transduction in mesenteric arteries from deoxycorticosterone acetate-salt hypertensive rats[J]. J Pharmacol Exp Ther, 1996, 277(2):1103-1113.
[18]Watts SW, Gilbert L, Webb RC. 5-Hydroxytryptamine2B receptor mediates contraction in the mesenteric artery of mineralocorticoid hypertensive rats[J]. Hypertension, 1995,26(6 Pt 2):1056-1059.
[19]Lawrie A, Spiekerkoetter E, Martinez EC, et al. Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease[J]. Circ Res, 2005, 97(3):227-235.
[20]Liu Y, Suzuki YJ, Day RM, et al. Rho kinase-induced nuclear translocation of ERK1/ERK2 in smooth muscle cell mitogenesis caused by serotonin[J]. Circ Res, 2004, 95(6):579-586.
[21]Kawut SM, Horn EM, Berekashvili KK, et al. Selective serotonin reuptake inhibitor use and outcomes in pulmonary arterial hypertension[J]. Pulm Pharmacol Ther, 2006, 19(5):370-374.
[22]Eddahibi S, Humbert M, Fadel E, et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension[J]. J Clin Invest, 2001, 108(8):1141-1150.
[23]Marcos E, Adnot S, Pham MH, et al. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension[J]. Am J Respir Crit Care Med, 2003, 168(4):487-493.
[24]Guignabert C, Raffestin B, Benferhat R, et al. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats[J]. Circulation, 2005, 111(21):2812-2819.
[25]Suzuki YJ, Day RM, Tan CC, et al. Activation of GATA-4 by serotonin in pulmonary artery smooth muscle cells[J]. J Biol Chem, 2003, 278(19):17525-17531.
[26]Cogolludo A, Moreno L, Lodi F, et al. Serotonin inhibits voltage-gated K⁺ currents in pulmonary artery smooth muscle cells: role of 5-HT_2A receptors, caveolin-1, and KV1.5 channel internalization[J]. Circ Res, 2006, 98(7):931-938.
[27]Herve P, Launay JM, Scrobohaci ML, et al. Increased plasma serotonin in primary pulmonary hypertension[J]. Am J Med, 1995, 99(3):249-254.
[28]Domenighetti G, Leuenberger P, Feihl F. Haemodynamic effects of ketanserin either alone or with oxygen in COPD patients with secondary pulmonary hypertension[J]. Monaldi Arch Chest Dis, 1997, 52(5):429-433.
[29]Macintyre PD, Bhargava B, Hogg KJ, et al. The effect of i.v. sumatriptan, a selective 5-HT₁-receptor agonist on central haemodynamics and the coronary circulation[J]. Br J Clin Pharmacol, 1992, 34(6):541-546.
[30]Launay JM, Hervé P, Peoc'h K, et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension[J]. Nat Med, 2002, 8(10):1129-1135.
[31]Porvasnik SL, Germain S, Embury J, et al. PRX-08066, a novel 5-hydroxytryptamine receptor 2B antagonist, reduces monocrotaline-induced pulmonary arterial hypertension and right ventricular hypertrophy in rats[J]. J Pharmacol Exp Ther, 2010, 334(2):364-372.