劉梅顏,張麗軍
· 論著 ·
藥物預(yù)處理對(duì)心肌梗死合并抑郁大鼠血清、血小板及腦組織5-羥色胺水平的影響
劉梅顏1,張麗軍1
目的探討不同藥物預(yù)處理對(duì)心肌梗死(心梗)、抑郁、心梗+抑郁大鼠血清、血小板、腦組織中的5-羥色胺(5-HT)水平的影響,以研究藥物預(yù)處理對(duì)心梗和抑郁的保護(hù)作用。方法將80只4周齡Sprague-Dawley(SD)大鼠隨機(jī)分為治療組和對(duì)照組,每組各40只,分別予益氣活血、改善微循環(huán)的中成藥(主要成分三七、人參等)或生理鹽水灌胃4周后,將治療組和對(duì)照組再隨機(jī)各分為4個(gè)亞組,每各亞組各10只,分別建立假手術(shù)、抑郁、心梗、心梗+抑郁四種動(dòng)物模型,最終每組中建模成功的大鼠數(shù)量如下,對(duì)照組:假手術(shù)組亞組8只(80%),抑郁亞組9只(90%),心梗亞組8只(80%),心梗+抑郁亞組8只(80%);治療組:假手術(shù)亞組9只(90%),抑郁亞組10只(100%),心梗亞組9只(90%),心梗+抑郁亞組8只(80%)。造模成功3 d后處死,測(cè)量各組大鼠血清、血小板及腦組織中5-HT水平。結(jié)果對(duì)照組的心梗、抑郁、心梗+抑郁亞組的血清5-HT水平、血小板5-HT水平均較假手術(shù)亞組下降(P<0.05);對(duì)照組的心梗亞組較假手術(shù)亞組腦組織5-HT水平下降,抑郁、心梗+抑郁亞組的5-HT水平,均較假手術(shù)亞組上升(P均>0.05)。治療組的心梗、抑郁、心梗+抑郁亞組的血清、腦組織5-HT水平,均較假手術(shù)組顯著上升,(P均<0.05);治療組心梗、抑郁、心梗+抑郁亞組的血小板5-HT水平,均較假手術(shù)組下降(P均<0.05)。治療組的假手術(shù)、心梗、抑郁及心梗+抑郁亞組的血清5-HT及血小板5-HT水平,均分別較對(duì)照組的相應(yīng)的4個(gè)亞組高(P均<0.05)。治療組的假手術(shù)、心梗、抑郁及心梗+抑郁亞組的腦組織5-HT水平,均分別較對(duì)照組的相應(yīng)的4個(gè)亞組低,但除抑郁亞組外其余差異均有統(tǒng)計(jì)學(xué)意義(P均<0.05)。結(jié)論本研究的藥物預(yù)處理能改善心梗、抑郁、心梗+抑郁等應(yīng)激造成的血清、血小板5-HT水平下降的情況,但對(duì)腦組織5-HT水平無(wú)顯著影響。
心肌梗死;抑郁;5-羥色胺
冠狀動(dòng)脈粥樣硬化性心臟病(冠心?。┦侨蚍秶鷥?nèi)導(dǎo)致人類死亡的首要原因[1]。冠心病常常和抑郁共病,約25.2%~40.3%的冠心病患者合并了抑郁癥[2],共病增加了患者的死亡率[3]。Chi等[4]研究發(fā)現(xiàn)心肌梗死(心梗)患者的抑郁發(fā)病率比正常人高,Niakan等[5]研究表明心?;颊咴诎l(fā)病后第15 d、第30 d抑郁的嚴(yán)重程度會(huì)增加。而抑郁是成年人患冠心病的獨(dú)立危險(xiǎn)因素,Waloszek等[6]臨床研究發(fā)現(xiàn)抑郁患者的血管情況較正常人差,故抑郁癥患者有更高的心臟病患病風(fēng)險(xiǎn),尤其是女性[7]。
心梗合并抑郁是雙心病的一種,雙心病即心理心臟疾病,心理問(wèn)題和心血管疾病,可以互為因果,互相影響,共同導(dǎo)致患者預(yù)后惡化,二者共病問(wèn)題已成為最嚴(yán)重的健康問(wèn)題之一[8],是目前臨床研究的熱點(diǎn),但二者共病的機(jī)制仍不清楚。本研究中的心梗合并抑郁屬于雙心病之一。抑郁是缺血性心臟病患者的心臟病事件發(fā)生和致死的獨(dú)立危險(xiǎn)因素[9]。目前,兩者共病的機(jī)制尚不清楚,其發(fā)病機(jī)制可能與人的情緒與心血管系統(tǒng)之間的深層聯(lián)系及神經(jīng)內(nèi)分泌調(diào)節(jié)有關(guān),如血管系統(tǒng)、自主神經(jīng)系統(tǒng)、下丘腦-垂體-腎上腺軸、免疫系統(tǒng)等[10]。有研究認(rèn)為,5-羥色胺(5-hydroxytryptamine,5-HT)升高介導(dǎo)的血小板聚集是抑郁合并心梗的潛在機(jī)制[11]。血小板的聚集與冠心病發(fā)病有關(guān)[12],血小板活性增高會(huì)增加心梗伴抑郁癥患者心臟病事件發(fā)生的幾率[7]。Vikenes等[13]研究認(rèn)為,全血5-HT水平的變化與心臟病事件的發(fā)生有關(guān)系。目前的研究認(rèn)為人體5-HT調(diào)節(jié)的異常是其共病的主要原因之一[14],前期研究發(fā)現(xiàn)抑郁合并心梗大鼠血清及血小板5-HT水平均出現(xiàn)下降,我們推測(cè)是因?yàn)樾墓<耙钟魬?yīng)激大量消耗了5-HT水平,使大鼠的機(jī)體活力下降,對(duì)此本研究將繼續(xù)探索此關(guān)系。中藥治療雙心病已取得一定的療效[15],本研究使用的藥物主要成分具有“益氣活血,養(yǎng)心安神”的作用,故對(duì)藥物預(yù)處理心梗合并抑郁大鼠后的5-HT水平進(jìn)行研究。
1.1 材料正常4周齡Sprague-Dawley(SD)大鼠80只,體重180~220 g,雌雄各半,購(gòu)自江蘇省醫(yī)學(xué)實(shí)驗(yàn)動(dòng)物中心。大鼠5-羥色胺ELISA試劑盒,產(chǎn)品編號(hào):EFXER 00123,購(gòu)自南京翼飛雪生物科技有限公司。治療組藥物的主要成分為三七、人參,來(lái)源于廣東太安堂藥業(yè)股份有限公司生產(chǎn)的心靈丸。
1.2 分組將80只SD大鼠隨機(jī)分為治療組和對(duì)照組,每組40只,治療組予藥物40 mg/kg與生理鹽水混勻灌胃,對(duì)照組予等量生理鹽水灌胃,4周后,建立4種動(dòng)物模型,兩組分別隨機(jī)分為四個(gè)亞組,每組各10只:①假手術(shù)亞組:常規(guī)開(kāi)胸后,不夾閉左前動(dòng)脈,關(guān)胸。②抑郁亞組:按照修正的Porsolt[16]方法,采用強(qiáng)迫游泳試驗(yàn)(forced swimming test,F(xiàn)ST)系統(tǒng)制造抑郁癥動(dòng)物模型,采用透明圓柱形Pyrex游泳筒,底部直徑21 cm,高46 cm,水溫23~25℃,水深30 cm,將大鼠置于圓柱形透明容器中,進(jìn)行15 min“前游泳”,然后將大鼠從泳池中取出,烘干。成模判斷標(biāo)準(zhǔn):“前游泳”應(yīng)激24 h后,將大鼠再次置于泳池中,進(jìn)行5 min“測(cè)試游泳”并錄像,測(cè)評(píng)大鼠游泳行為與不動(dòng)行為的頻率,分析干預(yù)措施對(duì)大鼠行為的影響[17]。③心肌梗死亞組:將100 mg氯胺酮與10 mg甲苯噻嗪混合于生理鹽水中,配制成 10 ml的麻醉合劑,根據(jù)小鼠體重,每10 g給予0.1 ml上述合劑,小鼠肌肉松弛充分后取仰臥位將頭部和四肢固定于手術(shù)臺(tái)上,參照Akbay[18]的手術(shù)方法構(gòu)建急性心肌梗塞大鼠動(dòng)物模型;造模成功的標(biāo)準(zhǔn):手術(shù)后大鼠心臟梗塞區(qū)域鮮紅色變成蒼白色,心肌紫紺,室壁活動(dòng)減弱;大鼠心電表現(xiàn)為ST段弓背抬高或(和)T波高聳或與其形成單向曲線[19]。④心梗合并抑郁亞組:在大鼠MI模型構(gòu)建3 d后,給予強(qiáng)迫游泳實(shí)驗(yàn)。由于實(shí)驗(yàn)過(guò)程中,有個(gè)別大鼠體質(zhì)稍差,或出現(xiàn)感染等導(dǎo)致死亡,故實(shí)際成模數(shù)量及成模率如下,對(duì)照組: 假手術(shù)組亞組8只(80%),抑郁亞組9只(90%),心梗亞組8只(80%),心梗+抑郁亞組8只(80%);治療組:假手術(shù)亞組9只(90%),抑郁亞組10只(100%),心梗亞組9只(90%),心梗+抑郁亞組8只(80%)。造模成功3 d后處死,測(cè)量各組大鼠血清、血小板及腦組織中5-HT的水平。
1.3 評(píng)價(jià)指標(biāo)及檢測(cè)方法所有動(dòng)物禁食12 h后,統(tǒng)一于早8點(diǎn)取材。大鼠30 mg/kg戊巴比妥鈉腹腔麻醉后,心臟取血2 ml的同時(shí)處死動(dòng)物。①血清的制備:1 ml血液37℃水浴30 min凝固后低速離心(2000~3000 轉(zhuǎn)/min)20 min,收集上清即為血清。②血小板的制備:取1 ml心臟血于EDTA-K2抗凝管中(BD公司,貨號(hào):367844),室溫下2000 轉(zhuǎn)/min離心15 min得到富含血小板血漿(PRP),取PRP再次4℃ 2000轉(zhuǎn)/min,離心10min,棄上清得到血小板。③腦組織勻漿:取大鼠皮層,稱重后加入10倍體積的磷酸緩沖鹽溶液(PBS),使用玻璃勻漿器在冰上反復(fù)研磨,制成組織勻漿液,4℃ 2000轉(zhuǎn)/min,離心20 min,取上清得到腦組織勻漿。二辛可酸(BCA)法測(cè)定蛋白濃度。④5-HT測(cè)定:應(yīng)用雙抗體夾心法測(cè)定標(biāo)本中5-HT水平,將標(biāo)準(zhǔn)品、等體積血清、血小板裂解液和等量腦組織勻漿液加入酶標(biāo)板(標(biāo)準(zhǔn)品和每個(gè)樣本做2個(gè)復(fù)孔),37℃孵育30 min,PBS洗板后再加入酶標(biāo)試劑孵育30 min,加入顯色液,10 min后用稀硫酸終止反應(yīng)。酶標(biāo)儀450 nm波長(zhǎng)下測(cè)定吸光度(OD值),通過(guò)標(biāo)準(zhǔn)曲線計(jì)算樣品中5-HT濃度(取兩個(gè)復(fù)孔的平均值),血清與血小板裂解液中的5-HT濃度為(pg/ml),腦組織勻漿中的5-HT濃度為(pg/mg protein)。
1.4 統(tǒng)計(jì)學(xué)分析采用SPSS 17.0軟件行數(shù)據(jù)處理與分析。計(jì)量資料以平均數(shù)±標(biāo)準(zhǔn)差(s)表示,兩組組間比較采用獨(dú)立t檢驗(yàn),多組間比較采用ANOVA單因素分析,其中兩兩比較采用LSD檢驗(yàn),以P<0.05為差異有統(tǒng)計(jì)學(xué)意義。
2.1 不同預(yù)處理組血清5-HT、血小板5-HT比較對(duì)照組心梗、抑郁、心梗+抑郁亞組的血清及血小板5-HT水平,均較假手術(shù)亞組顯著下降(P<0.05)。治療組心梗、抑郁、心梗+抑郁亞組的血清及血小板5-HT水平,均較假手術(shù)組顯著上升(P<0.05)。治療組的假手術(shù)、心梗、抑郁及心梗+抑郁亞組的血清及血小板5-HT水平,均分別較對(duì)照組的相應(yīng)的4個(gè)亞組高(P<0.05)(表1)。
2.2 不同預(yù)處理組腦組織5-HT比較對(duì)照組抑郁、心梗+抑郁亞組的5-HT水平較假手術(shù)及心梗亞組略有上升,但差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。治療組心梗、抑郁、心梗+抑郁亞組的5-HT水平,均較假手術(shù)亞組上升(P<0.05)。治療組的假手術(shù)、心梗、抑郁及心梗+抑郁亞組的腦組織5-HT水平,均分別較對(duì)照組的相應(yīng)的4個(gè)亞組低,其中除抑郁亞組外(P>0.05),其余組間比較差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)(表1)。
5-HT,又稱血清素,既是重要的血管調(diào)節(jié)物質(zhì),也是中樞神經(jīng)系統(tǒng)重要的神經(jīng)遞質(zhì)。5-HT主要由激活的血小板釋放[20],是一種強(qiáng)有力的血管活性因子,具有收縮和舒張血管的功能。5-HT對(duì)血管的作用主要取決于5-HT受體及內(nèi)皮功能[21]。當(dāng)內(nèi)皮功能完整時(shí),5-HT可舒張小血管,能使血管平滑肌和成纖維細(xì)胞增殖,血小板聚集,并能放大生長(zhǎng)因子的作用[11]。正常情況下,在機(jī)體應(yīng)激時(shí),5-HT反應(yīng)性增高,對(duì)外周血管及組織起到保護(hù)作用。然而,在持續(xù)應(yīng)激作用下,機(jī)體處于病理狀態(tài),如急性冠脈事件,5-HT過(guò)度增高,則會(huì)損傷內(nèi)皮功能,導(dǎo)致機(jī)體損傷。
研究表明,5-HT對(duì)心臟有直接的作用,心臟分布有多種5-HT受體,參與了高血壓、冠心病、心律失常和心肌缺血的發(fā)病[22]。EK等[23]研究發(fā)現(xiàn)冠心病病人的血循環(huán)的5-HT水平增高。機(jī)體處于應(yīng)激狀態(tài)時(shí),可引起中樞神經(jīng)遞質(zhì)5-HT發(fā)生變化,進(jìn)而引起抑郁癥、焦慮癥、精神分裂癥、躁狂、孤獨(dú)癥、肥胖癥、藥物成癮等多種心理和行為異常[24]。
本研究中生理鹽水預(yù)處理更接近于生理狀態(tài),經(jīng)生理鹽水預(yù)處理后的心梗、抑郁、心梗+抑郁亞組大鼠的血清5-HT水平、血小板5-HT水平,均較假手術(shù)亞組顯著下降,這表明應(yīng)激損傷會(huì)消耗血清中的5-HT,使血小板釋放儲(chǔ)存的5-HT,故5-HT水平下降。不同的應(yīng)激狀態(tài),均會(huì)帶來(lái)外周血及血小板5-HT的下降,但應(yīng)激程度不同,5-HT的下降程度不同。當(dāng)大鼠受到輕度應(yīng)激時(shí),如假手術(shù),其血清及血小板的5-HT相對(duì)較高;隨著應(yīng)激水平的提高,如抑郁時(shí),5-HT下降,應(yīng)激水平突然提高,如心梗,5-HT則明顯下降。這表明不同刺激程度的增加,無(wú)論是抑郁還是心梗均會(huì)帶來(lái)外周血及血小板的5-HT降低,致使對(duì)機(jī)體的保護(hù)作用下降。
表1 不同預(yù)處理后血清、血小板、腦組織5-HT水平比較(s)
表1 不同預(yù)處理后血清、血小板、腦組織5-HT水平比較(s)
注:5-HT:5-羥色胺;pg/mg protein:每毫克腦組織蛋白質(zhì)中5-HT含量;對(duì)照組中各亞組與假手術(shù)亞組5-HT比較,aP<0.05;治療組中各亞組與假手術(shù)亞組5-HT比較,bP<0.05;治療組與對(duì)照組同亞組5-HT比較,cP<0.05
組別 例數(shù) 血清5-HT(pg/ml) 血小板5-HT(pg/ml) 腦組織5-HT(pg/mg protein)對(duì)照組 —— — —假手術(shù)亞組 8 363.23±32.19 200.27±5.41 462.71±47.47心梗亞組 8 176.15±11.32a129.74±27.17a456.54±19.33抑郁亞組 9 194.69±5.09a175.15±4.70a493.42±63.26心梗+抑郁亞組 8 182.50±10.23a180.83±11.08a492.63±65.22治療組 —— — —假手術(shù)亞組 9 381.73±8.76 436.52±6.32 327.13±11.21心梗亞組 9 474.04±10.86bc340.45±17.99bc362.82±26.87bc抑郁亞組 10 456.33±23.12bc252.03±22.26bc456.33±23.12b心梗+抑郁亞組 8 441.76±23.38bc265.37±29.49bc428.18±21.05bc
本研究對(duì)治療組用藥物預(yù)處理干預(yù)。研究結(jié)果發(fā)現(xiàn),在用藥物預(yù)處理的實(shí)驗(yàn)組中,假手術(shù)、心梗、抑郁及心梗+抑郁亞組的血清5-HT及血小板5-HT水平,均分別較對(duì)照組相應(yīng)的4個(gè)亞組顯著升高,但藥物對(duì)不同應(yīng)激狀態(tài)的大鼠5-HT調(diào)節(jié)有差異,隨著應(yīng)激水平的增高,5-HT水平有下降趨勢(shì),如心梗+抑郁亞組5-HT的血清及血小板5-HT,均較心梗亞組明顯降低。這說(shuō)明藥物預(yù)處理能改善這種5-HT下降的情況,能普遍增加血清和血小板5-HT水平,可以促進(jìn)機(jī)體的保護(hù)和外周組織的修復(fù)。
本研究對(duì)腦組織5-HT進(jìn)行了檢測(cè),結(jié)果發(fā)現(xiàn)對(duì)照組的心梗亞組較假手術(shù)亞組下降,而抑郁、心梗+抑郁亞組的5-HT水平,均較假手術(shù)亞組上升,差異沒(méi)有統(tǒng)計(jì)學(xué)意義(P>0.05)。然而,通過(guò)治療組發(fā)現(xiàn),假手術(shù)、心梗、抑郁及心梗+抑郁亞組的腦組織5-HT水平,均分別較對(duì)照組的相應(yīng)的4個(gè)亞組低,其中除抑郁亞組外(P>0.05),其余亞組差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。藥物預(yù)處理對(duì)腦組織5-HT水平變化沒(méi)有顯著影響。
中醫(yī)認(rèn)為“心主血脈,心藏神,為君主之官”,雙心病的發(fā)生與“氣滯血瘀,心神失養(yǎng)”有關(guān),這與西醫(yī)的認(rèn)識(shí)有相通之處[25]。近年來(lái),中西醫(yī)結(jié)合防治雙心病已見(jiàn)顯著療效。本研究中所選用中成藥主要組成有三七、人參、珍珠等。具有“活血化瘀,益氣通脈,寧心安神”的作用,藥理研究表明其能降低動(dòng)脈壓,增加冠狀動(dòng)脈流量,擴(kuò)張外周血管,降低心臟后負(fù)荷,使心率減慢,心肌耗氧量降低,改善心肌供血。臨床上用于治療冠心病、抗焦慮抑郁等。本研究中藥物預(yù)處理減少了血清中的5-HT消耗,增加血小板對(duì)5-HT的儲(chǔ)備能力,故血小板中5-HT釋放減少,減少5-HT對(duì)血小板的激活,從而減少血小板聚集,防止血管由于突然的應(yīng)激而過(guò)度收縮,起到了保護(hù)心血管的作用。由此可見(jiàn)藥物對(duì)血清和血小板5-HT水平的調(diào)節(jié)有明顯的作用,可以促進(jìn)機(jī)體的保護(hù)和組織修復(fù)。
當(dāng)體內(nèi)5-HT水平降低時(shí),神經(jīng)元間信息交流就會(huì)延緩。腦內(nèi)5-HT的減少直接與抑郁狀態(tài)有關(guān),新型抗抑郁藥是以調(diào)節(jié)5-HT水平為靶點(diǎn)的,如五羥色胺再攝取抑制劑(SSRI)[26]。由于血液中的5-HT有99%儲(chǔ)存于血小板中,故有研究認(rèn)為腦組織5-HT水平的變化可以通過(guò)血小板5-HT水平反映出來(lái)[27]。本研究并沒(méi)有得到腦組織與血小板5-HT變化一致的結(jié)論,可能由于血腦屏障的存在,本研究中的藥物很難進(jìn)入腦組織中,對(duì)腦組織中的5-HT沒(méi)有影響,故中樞與外周5-HT水平的相關(guān)性仍有待研究。
綜上所述,不同的應(yīng)激狀態(tài),均會(huì)帶來(lái)外周血及血小板5-HT的下降,隨著應(yīng)激水平的提高,5-HT水平下降越明顯,使用藥物前期干預(yù),能改善應(yīng)激狀態(tài)下血清和血小板5-HT水平下降情況,能起到保護(hù)心血管的作用,對(duì)雙心病的防治有療效。而腦組織的5-HT變化與外周血不同,可能與5-HT轉(zhuǎn)運(yùn)體的功能有關(guān),本研究尚不能證實(shí)血小板5-HT水平變化能反映腦組織的5-HT的水平變化,其深層的機(jī)制仍有待更進(jìn)一步研究。
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本文編輯:張磊,姚雪莉
Effect of Medicine Pre-treatment on serotonin (5-HT) in Rats of Myocardial Infarction Co-exist with Depression
LIU Mei-yan*, ZHANG Li-jun.*Department of Cardiology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, 100029, China.
Corresponding author: Liu meiyan; E-mail: china_lmy@hotmail.com
ObjectiveTo explore the effect of different pre-treatments on serum 5-HT, platelet 5-HT and brain 5-HT in the Sprague-Dawley rats of myocardial infarction (MI), depression, and myocardial infarction coexist with depression (MI + depression), and study the effect of the drug in preventing MI and depression.Methods80 SD rats were allocated into pretreatment group and control group randomly. After 4 weeks’ pretreatment with Chinese patent medicine for benefiting qi and activing blood circulation and improving microcirculation system (include panax and ginseng etc.), then both of the two groups were established four models of shame subgroup, depression subgroup, myocardial infarction subgroup, MI + depression subgroup. The number of rats successfully modeled in control group was as follows: 8 rats in shame subgroup (80%), 9 rats in depression subgroup (90%), 8 rats in myocardial infarction subgroup (80%) and 8 rats in MI + depression subgroup (80%). The number of rats successfully modeled in pretreatment group was as follows: 9 rats in shame subgroup (90%), 10 rats in depression subgroup (100%), 9 rats in myocardial infarction subgroup (90%) and 8 rats in MI + depression subgroup (80%). All the rats were sacrificed 3 days later. 5-HT in serum, platelet, and brain of the rats in different groups were measured.ResultsIn control group, 5-HT in serum and platelet decreased significantly in MI, depression and MI + depression subgroup compared with shame subgroup (all P<0.05); 5-HT in brain of MI subgroup was lower than the shame subgroup, while the depression and MI + depression were higher, but without any significance (all P>0.05). In pretreatment group, 5-HT in serum and brain increased significantly in MI, depression and MI + depression subgroup compared with shame subgroup (all P<0.05); 5-HT in platelet of MI, depression and MI + depression subgroup were lower than the shame subgroup (all P<0.05). In pretreatment group, 5-HT in serum and platelet of the four subgroups were significantly higher than in control group (all P<0.05); 5-HT in brain of the four subgroups were lower than the control group and there was significance (P<0.05) except depression subgroup (P>0.05).Conclusions In this study, drugs could improve the decrease of 5-HT in serum and platelet due to myocardial infarction, depression and myocardial infarction co-exist with depression, but failed to influence 5-HT in brain.
Myocardial infarction; Depression; 5-HT
R541.4
A
1674-4055(2016)12-1458-05
1100029 北京,首都醫(yī)科大學(xué)附屬北京安貞醫(yī)院心臟中心
劉梅顏,E-mail:china_lmy@hotmail.com
10.3969/j.issn.1674-4055.2016.12.13