郭明，楊麗霞，周曉斌

充血性心力衰竭（congestive heart Failure, CHF，心衰），是各種心臟疾病發(fā)展的終末階段，嚴(yán)重影響著患者的預(yù)后和生存質(zhì)量。隨著循證醫(yī)學(xué)證據(jù)的不斷涌現(xiàn)，臨床上對(duì)CHF的治療模式已由以往的心－腎模式轉(zhuǎn)換為神經(jīng)－內(nèi)分泌綜合調(diào)控模式。血管緊張素Ⅱ受體拮抗劑（angiotensin Ⅱreceptor blockade，ARB）可有效阻斷腎素－血管緊張素－醛固酮系統(tǒng)，從而改善心臟功能，降低心衰患者的住院率和死亡率。因此ARB在CHF治療中的地位已提升至Ⅰ類推薦。以往基礎(chǔ)研究認(rèn)為，ARB治療心衰可能與避免或改善血管收縮、水鈉潴留、組織增生、膠原沉淀、細(xì)胞壞死和凋亡等有關(guān)，但至今對(duì)ARB治療心衰的確切機(jī)制仍不完全所知。本文對(duì)近年來ARB在CHF治療中的研究進(jìn)展作一綜述。

1 ARB治療心衰的相關(guān)臨床研究

1.1 ARB治療心衰的臨床研究 導(dǎo)致心力衰竭（HF）發(fā)生與發(fā)展的基本機(jī)制是心肌重構(gòu)，而腎素－血管緊張素－醛固酮（RAAS）系統(tǒng)的激活是引起心肌重構(gòu)的重要因素。ARB類藥物通過選擇性阻斷血管緊張素受體Ⅰ（AngⅠ）發(fā)揮抗RAAS系統(tǒng)的效應(yīng)，在臨床治療HF中受到廣泛重視，目前該領(lǐng)域一共有3大臨床研究。ELITE研究[1]發(fā)現(xiàn)氯沙坦較卡托普利可明顯降低老年心衰患者的死亡率，但后續(xù)研究[2]認(rèn)為，與卡托普利相比，氯沙坦并不能降低老年HF患者的全因死亡率，因此僅在患者不能耐受卡托普利時(shí)才選擇氯沙坦。Val-HeFT的亞組試驗(yàn)結(jié)果證明，在ACEI治療的基礎(chǔ)上聯(lián)合應(yīng)用ARB可以明顯延緩左心室重構(gòu)的發(fā)展[3]。迄今規(guī)模最大的以ARB治療HF的臨床試驗(yàn)CHARM-Added[4]和CHARM-Alternative也顯示，坎地沙坦可降低HF的發(fā)病率和死亡率[5]。

1.2 ARB與ACEI聯(lián)合運(yùn)用的現(xiàn)狀 目前血管緊張素轉(zhuǎn)換酶抑制劑（ACEI）仍然是治療HF的基石，但其并不能完全阻斷腎素－血管緊張素（RAS）系統(tǒng)。ACEI和ARB的聯(lián)合治療能更完全地阻斷RAS系統(tǒng)，較單獨(dú)用藥能更有效地減少血漿中醛固酮腦鈉尿肽[6-8]。因此，在ACEI治療的基礎(chǔ)上加用ARB可更有效地減少左心室重構(gòu)[9]，降低HF的發(fā)生率與死亡率。

最近一項(xiàng)Meta分析[10]討論了ACEI和ARB的聯(lián)合運(yùn)用與ACEI單獨(dú)運(yùn)用的利與弊。該分析共納入了8項(xiàng)實(shí)驗(yàn)，18061名患者。聯(lián)合終點(diǎn)包括總死亡率，心衰住院人數(shù)、全因住院人數(shù)；副作用包括腎功能惡化、有癥狀性低血壓、高鉀血癥、咳嗽、皮疹、血管性水腫等。結(jié)果顯示，與單獨(dú)運(yùn)用ACEI相比，聯(lián)合用藥可降低HF的住院率，但不能降低總死亡率和全因住院率，還會(huì)導(dǎo)致諸如腎功能惡化、低血壓和高血鉀傾向等副作用。然而基于目前的證據(jù)，聯(lián)合治療仍然是單獨(dú)運(yùn)用ACEI效果欠佳的替補(bǔ)方法，但要密切關(guān)注副作用的發(fā)生。

2 ARB治療心衰的相關(guān)基礎(chǔ)研究

2.1 改善心臟重構(gòu) 血管緊張素Ⅱ（Ang Ⅱ）在心血管系統(tǒng)內(nèi)可誘導(dǎo)產(chǎn)生NADPH氧化酶[11]，其超氧化作用可激活基質(zhì)金屬蛋白酶（MMPs）[12]和組織蛋白酶，參與心臟重構(gòu)過程，而ARB可通過調(diào)節(jié)MMPs改善心臟重構(gòu)[13]。

此外，Ahmed等[14]證明ARB可阻止HF大鼠心肌二聚糖的表達(dá)，延緩心肌間質(zhì)的纖維化進(jìn)程，從而改善心肌重構(gòu)。也有實(shí)驗(yàn)證明，AngⅡ的主要產(chǎn)物之一，TGF-β與COL1A1，1A2和3A1 mRNA的3’-未翻譯區(qū)相互協(xié)同，激活異源性核糖核蛋白A1，E1和K的合成，從而促進(jìn)心肌成纖維細(xì)胞合成Ⅰ、Ⅲ型膠原，加速心肌重構(gòu)[15]。Hiroyuki等在大鼠HF模型上證實(shí)，AngⅠ受體抑制劑（L-158809）可明顯減輕大鼠心肌纖維化。有研究發(fā)現(xiàn)通過用AT1受體抑制劑阻斷G蛋白信號(hào)途徑，也可抑制HF大鼠心肌的異常增生與纖維化，最終改善心功能并延緩心肌重構(gòu)[16]。近年研究顯示，HF和心肌細(xì)胞肥大均與促分裂原活化蛋白激酶（MAPKs）信號(hào)途徑激活有關(guān)[17,18]，而ARB則可通過抑制這一途徑發(fā)揮改善心肌肥厚、延緩HF的作用[19]。

2.2 阻斷RAAS系統(tǒng) HF的一個(gè)重要機(jī)制是心臟交感神經(jīng)興奮性（CSNA）增加。在HF初期其代償性增加血液量可使患者獲益；但隨著病情進(jìn)展，持續(xù)而強(qiáng)烈交感神經(jīng)興奮不僅會(huì)阻礙HF的恢復(fù)，同時(shí)也是猝死和其它并發(fā)癥的危險(xiǎn)因素，而AT1受體拮抗劑（纈沙坦）可使CSNA恢復(fù)正常[20]。

此外，在HF的發(fā)生過程中，化學(xué)感受器和壓力感受器均具有一定作用，心衰時(shí)動(dòng)脈內(nèi)的壓力感受反射受抑制，而化學(xué)感受反射加強(qiáng)。HF引起的組織缺氧可上調(diào)頸動(dòng)脈體內(nèi)化學(xué)感受器中的AT1受體，增加球細(xì)胞對(duì)AngⅡ的敏感性，AngⅡ還可通過增加Kv通道對(duì)缺氧的敏感性參與頸動(dòng)脈體調(diào)節(jié)[21]。Wang等通過向雙側(cè)孤束核部位注射氯沙坦，發(fā)現(xiàn)其可降低心衰動(dòng)物的基礎(chǔ)交感神經(jīng)活性，同時(shí)還可阻斷心交感傳入刺激引起的化學(xué)感受器反射[22]。除化學(xué)感受器外，ARB對(duì)壓力感受器也有作用，Ramchandra等證實(shí)厄貝沙坦可左移CSNA的壓力反射曲線，減少壓力反射引起的交感神經(jīng)興奮，但這一現(xiàn)象僅在外周AngⅡ刺激下有效，而對(duì)中樞AngⅡ升高引起的壓力反射并無明顯的抑制作用[23]。

HF與水鈉潴留密切相關(guān)，在左心室功能降低的情況下，機(jī)體通過激活精氨酸加壓素、神經(jīng)激素、RAAS系統(tǒng)和心房鈉尿肽導(dǎo)致水鈉潴留，以維持心輸出量和血壓。但是一旦發(fā)生水鈉潴留失代償則反而會(huì)增加HF的發(fā)病率和死亡率。Lutken的試驗(yàn)[24]證明，ARB可以逆轉(zhuǎn)AQP2、NKCC2 和NHE3、ENaC亞基和11-HSD2的表達(dá)，從而改善水鈉潴留的惡性循環(huán)。

2.3 調(diào)節(jié)一氧化氮（NO）的舒血管活性 一氧化氮合酶（NOS）有3種亞型：nNOS、iNOS 和eNOS，其中eNOS對(duì)心功能的作用尤為顯著。HF發(fā)生后，eNOS減少可致內(nèi)皮依賴性血管舒張障礙。用L-硝基-精氨酸甲脂（LZ）抑制NO后，會(huì)導(dǎo)致與心臟間質(zhì)纖維化有關(guān)炎癥反應(yīng)上調(diào)，心肌肥厚和血管平滑肌細(xì)胞增生。而Liu發(fā)現(xiàn)，在eNOS基因敲除的小鼠中，AngⅠ受體拮抗劑對(duì)心臟的保護(hù)作用幾乎消失[16]，提示NO有可能是AT1受體拮抗劑發(fā)揮保護(hù)HF作用的重要環(huán)節(jié)。ARB治療可阻斷AngⅡ介導(dǎo)的信號(hào)途徑，通過防止LZ+磷酸化肌球蛋白磷酸酶靶亞基1（MYPT1）表達(dá)的減少和削弱p42/44 MAPK信號(hào)級(jí)聯(lián)反應(yīng)的活化，來維持NO調(diào)節(jié)血管舒張的正常敏感度。

2.4 減輕超氧化應(yīng)激 有過去的幾年里，活性氧簇（reactive oxygen species，ROS）在HF中的作用受到密切關(guān)注[25]。氯沙坦可阻斷Ang II誘導(dǎo)ROS的形成[26]，而坎地沙坦則可保護(hù)RyR2的蛋白激酶A磷酸化，從而降低肌漿網(wǎng)對(duì)氧化應(yīng)激的耐受程度，減少Ca2+外漏的可能性[27]。

2.5 抑制炎癥反應(yīng) 有研究發(fā)現(xiàn)，在HF患者的循環(huán)血中促炎細(xì)胞因子普遍增高，如腫瘤壞死因子-α（TNF-α）、白細(xì)胞介素-1β（IL-1β）和 IL-6；且增高的程度與HF 的程度呈正相關(guān)，提示炎性細(xì)胞因子增加和交感神經(jīng)興奮可導(dǎo)致嚴(yán)重的室性心律失常，這也是HF病死率升高的主要原因之一。交感神經(jīng)興奮可調(diào)節(jié)中樞TNF-α和 IL-1β的表達(dá)增加，刺激ROS的產(chǎn)生，ROS又加強(qiáng)交感神經(jīng)興奮性，形成惡性循環(huán)導(dǎo)致HF加重。細(xì)胞因子的拮抗劑己酮可可堿（PTX）能夠大量減少HF大鼠中ROS的生成，直接或間接地減弱腎交感神經(jīng)活性[28,29]，從而降低氧化應(yīng)激反應(yīng)。AngⅡ可導(dǎo)致離體心臟標(biāo)本中TNF-α水平升高[30]，經(jīng)氯沙坦干預(yù)后可見TNF-α合成下降[31]，提示AngII與細(xì)胞因子在外周存在明顯的相互作用，而HF與TNF-α及IL-β明顯相關(guān)，細(xì)胞因子和RAS間同樣存在交互對(duì)話[32]，提示ARB可能通過交互對(duì)話抑制炎癥反應(yīng)來發(fā)揮抗HF的作用。深入研究發(fā)現(xiàn)，NF-κB也可調(diào)節(jié)RAS與促炎細(xì)胞因子之間的交互對(duì)話[33]，也為研究ARB調(diào)控兩者對(duì)話的機(jī)制提供了新的視角。

綜上所述，通過對(duì)近年來ARB治療CHF的相關(guān)臨床和基礎(chǔ)試驗(yàn)進(jìn)行總結(jié)，并從心室重構(gòu)，RAAS系統(tǒng)，NO的舒血管活性，超氧化應(yīng)激，炎癥反應(yīng)與AngII的交互對(duì)話等方面深入探討了ARB類藥物對(duì)治療CHF的可能機(jī)制，為ARB治療CHF的作用及其機(jī)制提供了更多的實(shí)驗(yàn)資料支持。

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