TRPM8通道激活剂薄荷醇对肺动脉高压大鼠的治疗作用  

Effect of menthol, a transient receptor potential melastatin-8 channel activator,on pulmonary arterial hypertensive rats

作　　者：李斌 邱浩恒 李壮 杨建钦 封文斌 刘晓晴 赵子建 穆云萍 李芳红 LI Bin;QIU Hao-heng;LI Zhuang;YANG Jian-qin;FENG Wen-bin;LIU Xiao-qing;ZHAO Zi-jian;MU Yun-ping;LI Fang-hong(School of Biomedical and Pharmaceutical Sciences,Guangdong University of Technology,Guangzhou 510006,China)

机构地区：[1]广东工业大学生物医药学院,广东广州510006

出　　处：《中国药理学通报》2023年第4期700-706,共7页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金青年项目(No 82100064);国家重点研发计划项目(No 2018YFA0800603);广东省重点领域研发计划项目(No 2019B020201015);广东省“珠江人才计划”项目(No 2016ZT06Y432);广东省自然科学基金面上项目(No 2020A1515011302)。

摘　　要：目的 探讨瞬时受体电位M8(transient receptor potential melastatin-8,TRPM8)通道激活剂薄荷醇(menthol)对野百合碱(monocrotaline, MCT)诱导的肺动脉高压(pulmonary arterial hypertension, PAH)大鼠的治疗作用。方法 SPF级雄性Sprague-Dawley大鼠随机分为6组:正常对照组、MCT组、MCT+menthol(1 mg·kg^(-1)·d^(-1))治疗组、MCT+menthol(2 mg·kg^(-1)·d^(-1))治疗组、MCT+menthol(5 mg·kg^(-1)·d^(-1))治疗组、MCT+menthol(10 mg·kg^(-1)·d^(-1))治疗组。腹腔注射MCT(50 mg·kg^(-1))构建PAH大鼠模型。造模1周后治疗组分别给予不同剂量的menthol灌胃治疗,持续2周。通过血流动力学检测、肺组织病理学染色、分子生物学技术,观察menthol对PAH大鼠右心室收缩压(RVSP)、右心室肥厚、肺小动脉(sPA)增殖重塑及钙通道蛋白(TRPM8、TRPC1、TRPC6)基因表达的影响。结果 与正常组相比,MCT组RVSP和右心质量指数(RVMI)明显升高,sPA(管腔直径50~150μm)管壁增厚,肺动脉中TRPM8表达明显降低,而TRPC1、TRPC6、心房钠尿肽(atrial natriuretic peptide, ANP)和脑钠肽(brain natriuretic peptide, BNP)表达明显上调,表明PAH大鼠造模成功;不同剂量menthol治疗均可明显降低PAH大鼠的RVSP和RVMI,改善sPA增生情况,上调TRPM8的表达,同时明显降低TRPC1、TRPC6、ANP及BNP的表达。结论 Menthol通过抑制TRPC1、TRPC6、ANP和BNP的表达,明显减轻MCT诱导的PAH和右心室肥大。Aim To investigate the effects of menthol,a transient receptor potential melastatin-8 channel activator,on treating pulmonary arterial hypertension(PAH)in PAH model rats caused by monocrotaline(MCT).Methods Male Sprague-Dawley rats were divided into six groups randomly(control group,MCT group,MCT+menthol 1 mg·kg^(-1)·d^(-1) group,MCT+menthol 2 mg·kg^(-1)·d^(-1) group,MCT+menthol 5 mg·kg^(-1)·d^(-1) group and MCT+menthol 10 mg·kg^(-1)·d^(-1) group).PAH model was constructed by intraperitoneal injection of MCT(50 mg·kg^(-1)).Seven days after drug injection,the rats were treated with menthol by intragastric administration,respectively,for two weeks.Hemodynamics and Hematoxylin-eosin staining were used to observe the right ventricle systolic pressure(RVSP),right ventricular hypertrophy and muscular small pulmonary arteries(sPA)remodeling.Experimental techniques of molecular biology were used to detect the expression of TRPM8,TRPC1 and TRPC6.Results Compared to control group,RVSP and RVMI were raised significantly after MCT injection,and MCT-treated rats exhibited massive remodeling of the muscular small PAs(vessel outer diameter of 50~150μm),TRPM8 expression was decreased in endothelium-denuded PAs,while TRPC1,TRPC6,atrial natriuretic peptide(ANP)and brain natriuretic peptide(BNP)expressions were increased indicating that the development of PAH in MCT-treated rats.Compared to MCT rats,the RVSP and RVMI were significantly reduced in menthol groups,and the ratio of luminal area over total area was enhanced.Furthermore,menthol inhibited the expression of TRPC1,TRPC6,ANP,BNP and enhanced the expression of TRPM8.Conclusions Menthol strongly alleviates MCT-induced PAH and right ventricular hypertrophy by inhibiting the expression of TRPC1,TRPC6,ANP and BNP.

关 键 词：TRPM8 薄荷醇 肺动脉高压 右心肥厚 钙通道 治疗 

分 类 号：R-332[医药卫生] R284.1R322.121R348.1R544