高血压抗AT1受体抗体阳性患者最优治疗方案研究及其机制探讨
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摘要
第一部分高血压抗AT1受体抗体阳性患者最优治疗方案研究:坎地沙坦西酯与咪达普利阶梯治疗高血压患者多中心随机盲法分组开放对照疗效评价试验
试验假设:探讨抗AT1受体抗体阳性高血压患者使用AT1受体阻滞剂坎地沙坦是否优于ACE抑制剂咪达普利,而在抗AT1受体抗体阴性高血压患者这一差异可能不明显或不如抗体阳性高血压患者显著。从而验证AT1受体阻滞剂具有阻滞抗AT1受体抗体激动剂样效应的作用。
试验设计和方法:本研究为多中心、随机、盲法分组、开放、平行对照临床试验。经筛选后的2级以上高血压患者随机入组,以ELISA法检测抗AT1受体抗体,给予坎地沙坦为基础或咪达普利为基础的阶梯治疗方案8周,根据患者抗AT1受体抗体检测结果和药物治疗方案,分为4个亚组进行统计分析:抗AT1受体抗体阳性坎地沙坦治疗组、抗AT1受体抗体阳性咪达普利治疗组、抗AT1受体抗体阴性坎地沙坦治疗组、抗AT1受体抗体阴性咪达普利治疗组,比较抗体阳性高血压患者之间及抗体阴性高血压患者之间坎地沙坦和咪达普利降压效果有无差异。
结果:在抗AT1抗体阳性高血压患者中,坎地沙坦治疗亚组降压效果优于咪达普利治疗亚组(坎地沙坦治疗亚组平均血压降幅35.9/17.6mmHg,咪达普利治疗组平均血压降幅28.8/13.4mmHg,P＜0.01)。而在抗AT1抗体阴性高血压患者中,坎地沙坦治疗亚组平均血压降幅28.3/15.8mmHg,咪达普利治疗亚组平均血压降幅26.5/15.4mmHg,无明显差异(P＞0.05)。咪达普利治疗亚组联合用药明显多于坎地沙坦治疗亚组,(分别为94%和86%,P＜0.05)。在基础水平上,抗AT1受体抗体阳性高血压人群平均收缩压高于抗AT1受体抗体阴性高血压人群(分别为160.5±16.5mmHg和156.2±17.7mmHg,P=0.03)。治疗结束后,两药物组血压均控制良好,平均血压水平无显著差异(坎地沙坦药物治疗组平均血压:127.7/78.4mmHg,咪达普利药物治疗组平均血压129.2/79.0mmHg,P＞0.05)。并且,抗体滴度高低和坎地沙坦降压效果无明显相关。
结论:抗AT1抗体可能与高血压发病机制相关,在抗AT1抗体阳性高血压患者AT1受体拮抗剂坎地沙坦优于血管紧张素转化酶抑制剂咪达普利,而在AT1-AA阴性高血压人群中,两者降压效果无差异。为高血压的个体化治疗提供新策略和循证依据。
第二部分抗AT1受体抗体激动活性测定
目的:研究抗AT1受体抗体对成年大鼠心室肌细胞内游离钙离子浓度([Ca~(2+)]_i)的影响,从而验证抗AT1受体抗体具有激动剂样活性。
材料和方法:用AT_1受体胞外第2肽段合成肽免疫Wistar大鼠,以硫酸铵沉淀法粗提血清抗体后再以亲和层析法纯化抗体,并以ELISA法检测抗AT_1受体抗体,用Bradford的方法对抗体进行定量,SDS-聚丙烯凝胶电泳检测抗体纯度,以免疫组化方法检验抗体的免疫活性,以Fluo-3AM作为细胞内游离Ca~(2+)示踪剂,通过激光共聚焦显微镜检测分离的成年大鼠心室肌细胞[Ca~(2+)]_i的变化,以判断抗体活性,分AngⅡ组,抗AT_1受体抗体组,抗AT_1受体抗体+氯沙坦组和无关Ig G对照组。
结果:抗AT1受体抗体在免疫2周开始产生,8周时抗体滴度达到很高,免疫组化结果显示抗体具有较高的免疫活性,从10ml血浆中约提取0.3mg的抗体,SDS—PAGE检测结果提示抗体纯度很高,AngⅡ刺激后引起[Ca~(2+)]_i快速上升至峰值(157.4%±52.5%),随后快速下降;而在抗AT_1受体抗体刺激下,呈双相反应,[Ca~(2+)]_i快速上升至峰值(164.0%±34.0%),随后进入平台期(与AngⅡ组相比,P＞0.05,无统计学意义)。其效应部分被氯沙坦阻断(79.7%±13.2%,与抗AT1受体抗体组相比,有统计学意义,P＜0.05)。来自正常大鼠血清的IgG对[Ca~(2+)]_i浓度几乎无影响(3.8%±0.3%)。
结论:无钙的环境下,抗AT_1受体抗体可以引起大鼠心室肌细胞内[Ca~(2+)]_i浓度增加,呈快速的峰值和持续的平台期的双相反应,其后的平台期可能与RynR信使系统激活有关,其效应可被AT1受体阻滞剂氯沙坦所抑制,说明其效应经AT1受体介导;而AngⅡ引起的[Ca~(2+)]_i浓度升高呈现单峰型,可能与IP_3R激活相关;AT1-AA与AngⅡ引起[Ca~(2+)]_i升高的途径不同可能在其介导的下游信号分子表达中起着关键作用。
PartⅠCandesartan versus Imidapril Comparative Trial in Hypertensives with Anti-AT1-Receptor Autoantibodies
A Stepwise Drug Treatment,Randomized,Blinded Assignment,Open-label,Parallelgroup, Multicenter Clinical Trial
Objectives AngiotensinⅡand anti-AT1-receptor autoantibodies(AT1-AAs) are very important for the development of hypertension,and several antihypertensive drugs target these factors.Our aim was to determine whether AT1-AAs were related to the blood pressure lowering effect of angiotension receptor blockers(ARBs) in hypertensive target therapy.
Methods The candesartan versus imidapril comparative trial in hypertensives with AT1-AAs was a multicenter,randomized,blinded assignment,open-label,parallelgroup comparison clinical trial in 7 centers of Wuhan,China.511 patients with moderate-to-severe primary hypertension were randomized to treatment with the candesartan-based regimens or the imidapril-based regimens for 8 weeks.AT1-AAs were detected by ELISA method.According to the AT1-AA,patients were divided into positive or negative group of AT1-AA after therapy end.
Results The mean blood presure(BP) reduction in AT1-AA-positive hypertensives was lower in candesartan-based regimen subgroup than in imidapril-based regimen subgroup(SBP/DBP:-35.9/17.6 mmHg and -28.8/13.4 mmHg,respectively,P＜0.01). In contrast,the blood pressure response in the AT1-AA-negative subjects was equal between the candesaran subgroup and the imidapril subgroup(p＞0.05).The mean SBP was higher in the AT1-AA-positive group than in the AT1-AA-negative group at random entry(mean SBP:160.5±16.5 and 156.2±17.7mmHg,respectively;P=0.03); blood pressure was well controlled with both treatment-based regimens due to achieve BP control trial.The percentage of the AT1-AA-positive imidapril-treated patients who received other antihypertensive drugs was larger than that of the AT1 -AA-positive candesartan-treated patients(94%and 86%,respectively;P＜0.05).In addition,no relation was seen between the titer of AT1-AA and blood pressure response to candesartan.
Conclusions We found that AT1-AA was associated with the BP lowering response to candesartan,and confirmed that AT1-AA was a risk factor of hypertension.The findings offer a new tailoring treatment approach using AT1-AA to predict the hypertensive target therapy.
PartⅡ
Influence of the Anti-AT1-Receptor Autoantibodies on Cytosolic Free Calcium Concentration in Adult Rat Ventricular Myocytes
Objectives To study the effects of anti-AT1-receptor autoantibodies on dynamic changes of cytosolic free calcium concentration in isolated adult rat left ventricular myocytes.
Methods The peptide corresponding to the sequence of the second extracellular loop of rat AT1 receptor was synthesized by solid-phase peptide synthesis technique.The peptide was used as the antigen to immunize Wistar rats,and then the anti-AT1-receptor antibody was isolated from serum sample by saturated ammonium sulfate precipitation,and then purified by a CNBr-activated sepharose 4B affinity chromatography column.The quantity,purity,and concentration of the purified antibodies were analyzed by Bradford method,SDS-PAGE and ELISA respectively,and the antibodies were used to prove the affinity with AT1-receptor in the rat ventricular myocytes by immunocytochemistry.By using laser scanning confocal microscope,the[Ca~(2+)]_i fluorescence signal change in isolated rat left ventricular myocytes was investigated by loading with[Ca~(2+)]_i indicator fluo-3/AM,and four groups were divided:(1) AngⅡgroup;(2) anti-AT1 receptor autoantibody group;(3) anti-AT1 receptor autoantibody+ losartan group;(4) control group.
Results Anti-AT1-receptor autoantibodies were detected in immunized rats 2 weeks after immunization,with the titers gradually increasing in the first 8 weeks.0.3mg purified anti-AT1-receptor autoantibodies could be obtained from 10ml sera.AngⅡcaused a large transient spiking of[Ca~(2+)]_i which followed by a rapid decrease in[Ca~(2+)]_i (157.4%±52.5%),while in anti-AT1-receptor autoantibody group,we observed a sustained elevated in[Ca~(2+)]_i after the transient spiking like AngⅡgroup(164.0%± 34.0%,compared with AngⅡgroup,p＞0.05);and the effect was partly antagonized by losartan(79.7%±13.2%,compared with the anti-AT1-receptor autoantibody group,p＜0.05).
Conclusions Both AngⅡand anti-AT1-receptor autoantibodies could elevated[Ca~(2+)]_i concentration of adult rat ventricular myocytes.But the effect of anti-AT1-receptor autoantibodies was more sustained,and could be attenuated by AT_1 receptor antagonist, and it is also suggest that ventricular myocytes of rat respond to anti-AT1-receptor autoantibodies with a increase of[Ca~(2+)]_i via an AT_1 receptor,and the changes of[Ca~(2+)]_i mainly depend on the release of intracellular stores.
试验假设:探讨抗AT1受体抗体阳性高血压患者使用AT1受体阻滞剂坎地沙坦是否优于ACE抑制剂咪达普利,而在抗AT1受体抗体阴性高血压患者这一差异可能不明显或不如抗体阳性高血压患者显著。从而验证AT1受体阻滞剂具有阻滞抗AT1受体抗体激动剂样效应的作用。
试验设计和方法:本研究为多中心、随机、盲法分组、开放、平行对照临床试验。经筛选后的2级以上高血压患者随机入组,以ELISA法检测抗AT1受体抗体,给予坎地沙坦为基础或咪达普利为基础的阶梯治疗方案8周,根据患者抗AT1受体抗体检测结果和药物治疗方案,分为4个亚组进行统计分析:抗AT1受体抗体阳性坎地沙坦治疗组、抗AT1受体抗体阳性咪达普利治疗组、抗AT1受体抗体阴性坎地沙坦治疗组、抗AT1受体抗体阴性咪达普利治疗组,比较抗体阳性高血压患者之间及抗体阴性高血压患者之间坎地沙坦和咪达普利降压效果有无差异。
结果:在抗AT1抗体阳性高血压患者中,坎地沙坦治疗亚组降压效果优于咪达普利治疗亚组(坎地沙坦治疗亚组平均血压降幅35.9/17.6mmHg,咪达普利治疗组平均血压降幅28.8/13.4mmHg,P＜0.01)。而在抗AT1抗体阴性高血压患者中,坎地沙坦治疗亚组平均血压降幅28.3/15.8mmHg,咪达普利治疗亚组平均血压降幅26.5/15.4mmHg,无明显差异(P＞0.05)。咪达普利治疗亚组联合用药明显多于坎地沙坦治疗亚组,(分别为94%和86%,P＜0.05)。在基础水平上,抗AT1受体抗体阳性高血压人群平均收缩压高于抗AT1受体抗体阴性高血压人群(分别为160.5±16.5mmHg和156.2±17.7mmHg,P=0.03)。治疗结束后,两药物组血压均控制良好,平均血压水平无显著差异(坎地沙坦药物治疗组平均血压:127.7/78.4mmHg,咪达普利药物治疗组平均血压129.2/79.0mmHg,P＞0.05)。并且,抗体滴度高低和坎地沙坦降压效果无明显相关。
结论:抗AT1抗体可能与高血压发病机制相关,在抗AT1抗体阳性高血压患者AT1受体拮抗剂坎地沙坦优于血管紧张素转化酶抑制剂咪达普利,而在AT1-AA阴性高血压人群中,两者降压效果无差异。为高血压的个体化治疗提供新策略和循证依据。
第二部分抗AT1受体抗体激动活性测定
目的:研究抗AT1受体抗体对成年大鼠心室肌细胞内游离钙离子浓度([Ca~(2+)]_i)的影响,从而验证抗AT1受体抗体具有激动剂样活性。
材料和方法:用AT_1受体胞外第2肽段合成肽免疫Wistar大鼠,以硫酸铵沉淀法粗提血清抗体后再以亲和层析法纯化抗体,并以ELISA法检测抗AT_1受体抗体,用Bradford的方法对抗体进行定量,SDS-聚丙烯凝胶电泳检测抗体纯度,以免疫组化方法检验抗体的免疫活性,以Fluo-3AM作为细胞内游离Ca~(2+)示踪剂,通过激光共聚焦显微镜检测分离的成年大鼠心室肌细胞[Ca~(2+)]_i的变化,以判断抗体活性,分AngⅡ组,抗AT_1受体抗体组,抗AT_1受体抗体+氯沙坦组和无关Ig G对照组。
结果:抗AT1受体抗体在免疫2周开始产生,8周时抗体滴度达到很高,免疫组化结果显示抗体具有较高的免疫活性,从10ml血浆中约提取0.3mg的抗体,SDS—PAGE检测结果提示抗体纯度很高,AngⅡ刺激后引起[Ca~(2+)]_i快速上升至峰值(157.4%±52.5%),随后快速下降;而在抗AT_1受体抗体刺激下,呈双相反应,[Ca~(2+)]_i快速上升至峰值(164.0%±34.0%),随后进入平台期(与AngⅡ组相比,P＞0.05,无统计学意义)。其效应部分被氯沙坦阻断(79.7%±13.2%,与抗AT1受体抗体组相比,有统计学意义,P＜0.05)。来自正常大鼠血清的IgG对[Ca~(2+)]_i浓度几乎无影响(3.8%±0.3%)。
结论:无钙的环境下,抗AT_1受体抗体可以引起大鼠心室肌细胞内[Ca~(2+)]_i浓度增加,呈快速的峰值和持续的平台期的双相反应,其后的平台期可能与RynR信使系统激活有关,其效应可被AT1受体阻滞剂氯沙坦所抑制,说明其效应经AT1受体介导;而AngⅡ引起的[Ca~(2+)]_i浓度升高呈现单峰型,可能与IP_3R激活相关;AT1-AA与AngⅡ引起[Ca~(2+)]_i升高的途径不同可能在其介导的下游信号分子表达中起着关键作用。
PartⅠCandesartan versus Imidapril Comparative Trial in Hypertensives with Anti-AT1-Receptor Autoantibodies
A Stepwise Drug Treatment,Randomized,Blinded Assignment,Open-label,Parallelgroup, Multicenter Clinical Trial
Objectives AngiotensinⅡand anti-AT1-receptor autoantibodies(AT1-AAs) are very important for the development of hypertension,and several antihypertensive drugs target these factors.Our aim was to determine whether AT1-AAs were related to the blood pressure lowering effect of angiotension receptor blockers(ARBs) in hypertensive target therapy.
Methods The candesartan versus imidapril comparative trial in hypertensives with AT1-AAs was a multicenter,randomized,blinded assignment,open-label,parallelgroup comparison clinical trial in 7 centers of Wuhan,China.511 patients with moderate-to-severe primary hypertension were randomized to treatment with the candesartan-based regimens or the imidapril-based regimens for 8 weeks.AT1-AAs were detected by ELISA method.According to the AT1-AA,patients were divided into positive or negative group of AT1-AA after therapy end.
Results The mean blood presure(BP) reduction in AT1-AA-positive hypertensives was lower in candesartan-based regimen subgroup than in imidapril-based regimen subgroup(SBP/DBP:-35.9/17.6 mmHg and -28.8/13.4 mmHg,respectively,P＜0.01). In contrast,the blood pressure response in the AT1-AA-negative subjects was equal between the candesaran subgroup and the imidapril subgroup(p＞0.05).The mean SBP was higher in the AT1-AA-positive group than in the AT1-AA-negative group at random entry(mean SBP:160.5±16.5 and 156.2±17.7mmHg,respectively;P=0.03); blood pressure was well controlled with both treatment-based regimens due to achieve BP control trial.The percentage of the AT1-AA-positive imidapril-treated patients who received other antihypertensive drugs was larger than that of the AT1 -AA-positive candesartan-treated patients(94%and 86%,respectively;P＜0.05).In addition,no relation was seen between the titer of AT1-AA and blood pressure response to candesartan.
Conclusions We found that AT1-AA was associated with the BP lowering response to candesartan,and confirmed that AT1-AA was a risk factor of hypertension.The findings offer a new tailoring treatment approach using AT1-AA to predict the hypertensive target therapy.
PartⅡ
Influence of the Anti-AT1-Receptor Autoantibodies on Cytosolic Free Calcium Concentration in Adult Rat Ventricular Myocytes
Objectives To study the effects of anti-AT1-receptor autoantibodies on dynamic changes of cytosolic free calcium concentration in isolated adult rat left ventricular myocytes.
Methods The peptide corresponding to the sequence of the second extracellular loop of rat AT1 receptor was synthesized by solid-phase peptide synthesis technique.The peptide was used as the antigen to immunize Wistar rats,and then the anti-AT1-receptor antibody was isolated from serum sample by saturated ammonium sulfate precipitation,and then purified by a CNBr-activated sepharose 4B affinity chromatography column.The quantity,purity,and concentration of the purified antibodies were analyzed by Bradford method,SDS-PAGE and ELISA respectively,and the antibodies were used to prove the affinity with AT1-receptor in the rat ventricular myocytes by immunocytochemistry.By using laser scanning confocal microscope,the[Ca~(2+)]_i fluorescence signal change in isolated rat left ventricular myocytes was investigated by loading with[Ca~(2+)]_i indicator fluo-3/AM,and four groups were divided:(1) AngⅡgroup;(2) anti-AT1 receptor autoantibody group;(3) anti-AT1 receptor autoantibody+ losartan group;(4) control group.
Results Anti-AT1-receptor autoantibodies were detected in immunized rats 2 weeks after immunization,with the titers gradually increasing in the first 8 weeks.0.3mg purified anti-AT1-receptor autoantibodies could be obtained from 10ml sera.AngⅡcaused a large transient spiking of[Ca~(2+)]_i which followed by a rapid decrease in[Ca~(2+)]_i (157.4%±52.5%),while in anti-AT1-receptor autoantibody group,we observed a sustained elevated in[Ca~(2+)]_i after the transient spiking like AngⅡgroup(164.0%± 34.0%,compared with AngⅡgroup,p＞0.05);and the effect was partly antagonized by losartan(79.7%±13.2%,compared with the anti-AT1-receptor autoantibody group,p＜0.05).
Conclusions Both AngⅡand anti-AT1-receptor autoantibodies could elevated[Ca~(2+)]_i concentration of adult rat ventricular myocytes.But the effect of anti-AT1-receptor autoantibodies was more sustained,and could be attenuated by AT_1 receptor antagonist, and it is also suggest that ventricular myocytes of rat respond to anti-AT1-receptor autoantibodies with a increase of[Ca~(2+)]_i via an AT_1 receptor,and the changes of[Ca~(2+)]_i mainly depend on the release of intracellular stores.
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13、Dechend R,Homuth V,Wallukat G,Kreuzer J,Park JK,Theuer J,Juepner A,Gulba DC,Mackman N,Haller H,Luft FC.AT1 receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor.Circulation 2000;101:2382-7.
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