缺血后处理减轻大鼠肥厚心肌缺血再灌注损伤的观察

目的探讨缺血后处理对心肌肥厚大鼠离体心脏缺血再灌注损伤的影响及其信号机制。方法通过腹主动脉结扎建立大鼠心肌肥厚模型,用Landendorff装置建立心肌肥厚大鼠离体心脏缺血再灌注模型。观察缺血后处理对心肌肥厚大鼠离体缺血再灌注心脏左心室收缩压,冠状动脉流量,肌酸磷酸激酶和乳酸脱氢酶释放,心肌梗死范围,心肌组织中蛋白激酶B／Akt（Akt）、糖原合成酶激酶-3β（GSK-3β）磷酸化的影响。结果与缺血再灌注对照组相比,缺血后处理组心脏左心室收缩压、冠状动脉流量显著高,冠状动脉循环流出液中肌酸磷酸激酶、乳酸脱氢酶含量低,心肌梗死范围减小,心肌组织中磷酸化Akt（Ser473）、磷酸化GSK-3β（Set9）水平高,磷脂酰肌醇-3激酶（PI3K）抑制剂渥曼青霉素（wortmannin）能够抑制缺血后处理所致的磷酸化Akt（Ser473）、磷酸化GSK-3β（Set9）水平升高,但只能部分消除缺血后处理的心脏保护效应。结论缺血后处理能够减轻心肌肥厚大鼠离体心脏缺血再灌注损伤,PI3K／Akt／GSK-3信号途径参与介导缺血后处理对离体缺血再灌注肥厚心肌的保护作用。     

缺血预处理减轻肥厚心肌缺血再灌注损伤及其信号途径

目的探讨缺血预处理(IPC)对肥厚心肌体外缺血再灌注(IR)损伤的影响及其信号机制。方法48只心肌肥厚大鼠随机分为4组:IR对照组I、PC组I、PC加磷脂酰肌醇-3激酶(PI3K)抑制剂Wortmannin处理组、Wortmannin处理对照组,观察IPC对心肌肥厚大鼠体外IR心脏左心室收缩压、冠状动脉流量、肌酸磷酸激酶(CPK)和乳酸脱氢酶(LDH)释放、心肌梗死范围以及心肌蛋白激酶B(Akt)、糖原合成酶激酶-3β(GSK-3β)磷酸化的影响。结果与IR对照组比较,IPC组心脏左心室收缩压、冠状动脉流量显著提高,CPK、LDH释放减少,心肌梗死范围减小,心肌Akt、GSK-3β磷酸化水平增高,Wortmannin能够抑制IPC所致的Akt、GSK-3β磷酸化,但只能部分消除IPC的心脏保护效应。结论IPC能够减轻心肌肥厚大鼠体外心脏IR损伤,PI3K、Akt、GSK-3β信号途径参与介导IPC对体外IR肥厚心肌的保护作用。     

卡托普利对大鼠肥厚心肌受缺血再灌注损伤的保护作用及其机制探讨

腹主动脉缩窄致大鼠心肌肥厚模型作离体工作心脏灌流，观察卡托普利对大鼠肥厚心肌受缺血再灌注损伤的保护作用及血管紧张素Ⅱ（ＡｎｇⅡ）的影响。结果表明：在心脏停跳液及再灌注Ｋ－Ｈ液中加入卡托普利（２３．０μｍｏｌ／Ｌ）可明显改善肥厚心肌缺血再灌注后心功能的恢复，增加冠状动脉血流量，降低心肌组织乳酸、Ｎａ＋、Ｃａ２＋及ＭＤＡ的含量，并使心肌组织ＣＫ酶峰前移；而ＡｎｇⅡ（１０ｎｍｏｌ／Ｌ）可减弱卡托普利对肥厚心肌受缺血再灌注损伤的保护作用。我们认为，卡托普利对肥厚心肌受缺血再灌注损伤有保护作用，其机制可能与抑制心脏肾素－血管紧张素系统有关     

血管紧张素-(1-7)与血管紧张素Ⅱ在心肌缺血/再灌注损伤中的作用

目的 :探讨血管紧张素 (1 7) [Ang (1 7) ]与血管紧张素Ⅱ (AngⅡ )在心肌缺血 再灌注损伤中的作用。方法 :离体大鼠心脏置于Langendorff装置上 ,采用主动脉逆灌法 ,结扎左冠状动脉前降支 15min后 ,剪断丝线再灌流 30min ,造成心肌缺血 再灌注损伤模型。在缺血期和再灌注期分别用含有Ang (1 7)或AngⅡ的缓冲液灌注 ,浓度均为 1.0nmol L ,观察它们对再灌注期室性心律失常、左室收缩压 (LVSP)及冠状动脉流量的影响。结果 :AngⅡ明显增加再灌注期室性心律失常程度记分 ,不利于再灌注期冠状动脉流量和LVSP的恢复 ;而Ang (1 7)可减少再灌注期室性心律失常程度记分 ,促进再灌注期冠状动脉流量的恢复 ,并能预防再灌注期LVSP进一步下降。一氧化氮合酶抑制剂L 硝基精氨酸甲酯可阻断Ang (1 7)对再灌注期冠状动脉流量的影响 ,但不能改变其对再灌注期心律失常及LVSP的影响。结论 :外源性Ang (1 7)在心肌缺血 再灌注损伤中的作用不同于AngⅡ ,能减少缺血再灌注损伤。它对再灌注期冠状动脉流量的影响可能与一氧化氮的合成与释放有关     

含抑肽酶灌注液减轻缺血再灌注心肌的损伤

目的　观察抑肽酶等药物对缺血再灌注离体兔心的影响。方法　 2 4只家兔随机分为两组 :对照组 (B组 )将离体心脏置于 L angendorfl装置 ,经主动脉逆行灌注克氏液 ,灌注 30 min后 ,用 Thomas灌注停跳 40 min,最后再恢复灌注 30 min。用药组 (A组 )克氏液中加入抑肽酶及山莨菪碱。缺血前及再灌注期记录左心室功能及冠状动脉血管阻力 ,并行心肌超微结构观察。结果　再灌注后 30 min,A组左心室功能明显高于 B组 (P<0 .0 5 ) ;收集的灌注液中肌酸磷酸激酶 (CK)及乳酸脱氢酶 (L DH)较 B组明显减少 ;超微结构改善也优于 B组。结论　抑肽酶对缺血再灌注心肌功能有明显保护作用     

卡托普利对大鼠肥厚心肌受缺血再灌注损伤的保护作用及其机…

腹主动脉缩窄致大鼠心肌肥厚模型作离体工作心脏灌流，观察卡托普利对大鼠肥厚心肌受缺血再灌注损伤的保护作用及血管紧张素的影响。结果表明：在心脏停跳液及再灌注Ｋ－Ｈ液中加入卡托普利可明显改善肥厚心肌缺血再灌注后心功能的恢复，增加冠状动脉血流量，降低心肌组织乳酸，Ｎａ＾＋，Ｃａ＾２＋及ＭＤＡ的含量，并使心肌组织ＣＫ酶峰前移。     

新型卤酚化合物3',4'-二羟基-3-氯二苯甲酮对大鼠缺血/再灌注心肌的保护作用

目的 明确新型卤酚化合物3',4'-二羟基-3-氯二苯甲酮(LM46)对缺血/再灌注损伤后大鼠心肌的保护作用.方法 利用大鼠心脏局部缺血/再灌注模型,检测LM46处理后大鼠心肌梗死面积和血清酶学指标的变化.结果 在再灌注早期静脉给予LM46能有效减轻心肌缺血/再灌注损伤.表现为梗死面积减小,超氧化物歧化酶(SOD)活力升高,显著降低血清乳酸脱氢酶(LDH)、肌酸激酶(CK)、丙二醛(MDA)水平.结论 在5 mg/kg~15 mg/kg剂量范围内,LM46有显著的心肌保护作用.     

蛋白激酶A在缺血预处理抑制心肌细胞核因子-кB-DNA结合活性中的作用

目的:探讨蛋白激酶A在缺血预处理抑制心肌细胞核因子-кB-脱氧核糖核酸(DNA)(NF-кB-DNA)结合活性中的作用.方法:采用Langendorff离体心脏灌注模型.40只SD大鼠随机分为4组,缺血/再灌注组、缺血预处理组、蛋白激酶A抑制剂组(H89组)和脯氨酸二硫氨基甲酸组(PDTC组,核因子-кB抑制剂).在平衡期、复灌10 min、20 min、30 min记录心率、左心室发展压,在平衡期、复灌30 min时记录冠状动脉流量,测定冠状动脉流出液中乳酸脱氢酶和肌酸激酶含量.复灌30 min后留取心肌用蛋白质免疫印迹法(Western blot)检测磷酸化环腺苷酸反应元件结合蛋白[p-CBEB(Ser133)]含量,凝胶电泳迁移率法(EMSA)检测核因子-кB-DNA结合活性.结果:与缺血/再灌注组相比,缺血预处理组和PDTC组心肌细胞核内p-CREB(Ser133)含量升高了2.31倍和1.65倍;与缺血预处理组相比,H89组p-CBEB(Ser133)含量显著降低,差异均有统计学意义(P均<0.01).与缺血/再灌注组相比,缺血预处理组心肌细胞核内核因子-кB-DNA结合活性明显降低;与缺血预处理组相比,H89组和PDTC组核因子-кB-DNA结合活性显著升高,差异均有统计学意义(P<0.05～0.01).复灌30min时,与缺血预处理组相比,缺血/再灌注组、H89组和PDTC组心率、左心室发展压和冠脉流量明显降低,乳酸脱氢酶和肌酸激酶活性显著升高,差异均有统计学意义(P均<0.05～0.01).结论:缺血预处理可通过激活蛋白激酶A抑制核因子-кB-DNA结合活性减轻心肌缺血再灌注损伤.     

磷脂酰肌醇3激酶信号通路在缺血后适应中对大鼠心肌保护机制的研究

目的研究缺血后适应(IPost)对大鼠心肌保护作用及磷脂酰肌醇3激酶(PI3K/Akt)信号通路机制。方法将32只雄性Wistar大鼠随机分为缺血再灌注组(A组),IPost组(B组),IPost+Wortmannin组(C组)和缺血再灌注+SB216763组(D组),每组8只。测定各组左心室收缩压(LVSP)和再灌注30 min冠状动脉流出液中乳酸脱氢酶和肌酸激酶含量。并测定心肌梗死面积,对心肌进行免疫组织化学染色,观察Akt磷酸化和GSK-3β磷酸化的表达。结果与B组比较,A组LVSP明显降低,乳酸脱氢酶和肌酸激酶含量明显升高(P0.05);同时IPost干预减小了心肌梗死面积(47.3% vs 29.5%),B组Akt磷酸化和GSK-3β磷酸化表达增加。结论 IPost对体外大鼠缺血再灌注损伤有明确的保护作用。Wortmannin可削弱IPost的保护作用,SB216763具有模拟IPost的心肌保护作用,Akt和GSK-3β的磷酸化水平在IPost的心肌保护作用信号通道传导机制中具有重要地位。     

糖尿病对离体大鼠缺血后适应心肌保护作用的影响

目的探讨糖尿病对离体大鼠缺血后适应心肌保护作用的影响。方法诱导2型糖尿病大鼠模型,采用Langendorff离体心脏灌流法,全心停灌30min,复灌60min,制成心肌缺血模型;全心停灌30min后,给予再灌注10s、停灌10s6次循环,然后再灌注至60min,制备缺血后适应模型。测定血流动力学指标和复灌20min冠状动脉流出液中乳酸脱氢酶(LDH)、肌酸激酶(CK)的含量。实验结束分离出左心室心肌并横切成5片,并测定心肌梗死面积。结果糖尿病大鼠缺血后适应血流动力学无明显改善,心肌酶释放量未减低,心肌梗死面积未显著减少(50.1%±3.7%比45.7%±4.8%,P0.05)。结论缺血后适应对糖尿病大鼠离体心脏无保护作用。     

酪氨酸激酶和蛋白激酶C参与高铁血红素诱导的抗大鼠心肌缺血再灌注损伤

目的研究酪氨酸激酶和蛋白激酶C参与高铁血红素诱导血红素氧合酶1在对抗心肌缺血再灌注损伤中的作用及其机制。方法离体大鼠心脏行Langendorff灌流,给予30min缺血和2h再灌注,观察心室收缩功能、乳酸脱氢酶、肌酸激酶和心肌梗死面积等指标。结果腹腔注射高铁血红素24h后,可明显改善缺血再灌注心脏的收缩功能,减少再灌注期乳酸脱氢酶和肌酸激酶释放,缩小心肌梗死面积。在腹腔注射高铁血红素前给予酪氨酸激酶抑制剂Genistein和蛋白激酶C抑制剂Chelerythrine可阻断高铁血红素引起的心肌梗死面积缩小和心功能的改善。结论高铁血红素可诱导血红素氧合酶1活性增加并对抗心肌缺血再灌注损伤,其作用与酪氨酸激酶和蛋白激酶C的激活有关。     

法舒地尔对大鼠离体心脏缺血/再灌注损伤的保护作用

目的观察盐酸法舒地尔对大鼠离体心脏缺血/再灌注（I/R）损伤是否有保护作用。方法SD大鼠19只,随机分为3组:I/R组、I/R+F组和对照组。用改良的Langendorff灌流装置,用K-H液行主动脉逆行灌流,建立大鼠离体心脏I/R损伤实验模型。I/R组预灌流20 min,停灌45 min,再灌30 min;I/R+F组于再灌注时在灌流液中加入盐酸法舒地尔注射液（10 mg/kg）;对照组连续灌流95 min。连续记录左心室收缩功能曲线,收集冠脉流出液,检测冠脉流出液中乳酸脱氢酶（LDH）、肌酸激酶（CK）、肌红蛋白（Mb）漏出量以及心肌细胞内钙、心肌组织一氧化氮（NO）含量和髓过氧化物酶（MPO）活力。结果心肌缺血使冠脉流出量减少,LDH、CK、Mb增加,再灌注后冠脉流出量进一步减少,LDH、CK、Mb进一步增加,同时增加细胞内钙,增加MPO活力,减少NO生成。盐酸法舒地尔逆转再灌注后冠脉流出量减少和LDH、CK和Mb漏出增加,降低细胞内钙、MPO活力,逆转NO生成减少。I/R使左室发展峰压平均值、平均±dp/dtmax均下降,盐酸法舒地尔对左室发展峰压的改变无明显影响,但改善±dp/dtmax降低。结论盐酸法舒地尔对心肌I/R损伤有保护作用,增强I/R引起的"无复流"现象和心肌收缩能力降低的恢复,此作用与逆转NO生成减少、MPO活性增高和细胞内钙超载等因素有关。     

再灌注损伤抢救激酶对小鼠缺血后适应心肌再灌注损伤中的减轻作用

目的 研究缺血后适应(IPC)对离体小鼠心肌缺血再灌注(I/R)损伤的作用及其影响因素,探讨再灌注损伤抢救激酶在IPC心肌保护中的作用.方法 建立Langendofff小鼠心肌I/R模型,全心缺血30 min后分为6组[(1)对照组,(2)3次IPC组(采取缺血10 s及再灌注10 s的3次IPC周期),(3)6次IPC组(采取缺血10 s及再灌注10 s的6次IPC周期),(4)延迟IPC组(恢复再灌注1 min后进行IPC),(5)IPC+PD98059组,(6)I/R+PD98059组],随后再灌注2 h;观察IPC对心脏血流动力学、心肌酶的释放、心肌超氧化物歧化酶活性和丙二醛的含量、梗死心肌范围的影响以及与细胞外信号调节激酶(ERK1/2)、磷脂酰肌醇3激酶-蛋白激酶B表达水平的关系.结果 与对照组比较,3次IPC组和6次IPC组小鼠心脏血流动力学显著改善,心肌酶释放减少,心肌丙二醛减少、超氧化物歧化酶活性增加,心肌梗死范围减小.6次与3次IPC周期的保护作用相似.而IPC作用在恢复再灌注1 min后消失.3次IPC组和6次iPC组心肌的ERK1/2磷酸化水平显著增高,蛋白激酶B磷酸化水平无明显变化.PD98059显著抑制IPC所致的ERK1/2的磷酸化,并能消除IPC对心肌的保护作用.结论 IPC能有效地减轻离体小鼠心肌缺血再灌注损伤,增加IPC的周期数并没有扩大保护作用,延迟IPC没有产生类似的保护作用.ERK1/2细胞信号途径参与介导IPC对离体心脏缺血再灌注心肌的保护作用.     

Non-angiogenic FGF-2 protects the ischemic heart from injury, in the presence or absence of reperfusion

OBJECTIVE: Fibroblast growth factor-2 (FGF-2), given during ischemia or during reperfusion of the ischemic heart is cardioprotective, but its mitogenic activity may limit possible clinical applications. We have tested the cardioprotective potential of a non-mitogenic FGF-2 mutant (S117A) that no longer activates casein kinase 2 (CK2) in both acute and long-term studies. METHODS AND RESULTS: To test effects during reperfusion, the ex vivo rat heart, subjected to 30 min of global ischemia and 60 min of reperfusion was used. S117A FGF-2 administered during reperfusion protected against myocardial contractile dysfunction, activated protein kinase C and decreased the release of cytochrome C in the cytosol. To study effects on ischemic myocytes in the absence of reperfusion, myocardial infarction (MI) was induced in the rat model by irreversible left coronary ligation. S117A-, wild type (wt)-FGF-2 or saline, were administered by intramyocardial injection into the ischemic ventricular wall. One day later, infarct size (assessed by tetrazolium staining), and plasma cardiac troponin T levels (assessed by Western blotting) were significantly decreased in the S117A FGF-2-, compared to the saline-treated group. Systolic pressure, rates of contraction and relaxation and developed pressure, assessed in the Langendorff mode, were significantly improved in the S117-FGF-2 group. Improved ejection fraction and fractional shortening in the S117A-treated group were maintained up to, but not beyond, 7 days post-MI. In comparison, improvements were maintained in the wt-FGF-2-treated group at least up to 6 weeks post-MI. At 6 weeks post-MI, small vessel density (assessed by immunofluorescence-based detection) in the scar bordering viable myocardium was similar between S117A-FGF-2- and saline-treated hearts, but significantly increased in the wt-FGF-2-treated group. This was accompanied by increased coronary flow in the wt-, but not S117A-FGF-2-treated hearts, compared to controls. CONCLUSION: The ability of FGF-2, administered during ischemia or during reperfusion, to protect the myocardium acutely from tissue loss and dysfunction is independent of its potential for CK2 activation and angiogenesis. Non-angiogenic S117A-FGF-2 may be considered in therapies aiming for acute prevention of reperfusion-associated pathologies, especially in cases where use of mitogens is counter-indicated.     

Selective modulation of endogenous nitric oxide formation in ischemia/reperfusion injury in isolated rat hearts

The role of nitric oxide (NO) in ischemia/reperfusion injury is controversial. We tested the role of inducible NOS (iNOS) in the ischemia/reperfusion injury in isolated rat hearts using the selective iNOS inhibitor S-methylisothiourea sulfate (SMT) and the non-selective NOS inhibitor N^G-nitro-L-arginine methyl ester (L-NAME). After 15 min of stabilization in Langendorff mode, hearts were perfused either with normal Krebs-Henseleit buffer, buffer containing 100 μM L-NAME, 0.5 μM SMT or 50 μM SMT for 5 min and were subjected to 25 min of ischemia followed by 30 min of reperfusion. Left ventricular developed pressure (LVDP) and total coronary flow (CF) were recorded continuously. After ischemia/reperfusion, a marked expression of iNOS protein was demonstrated by Western blotting, while virtually no iNOS protein was present in hearts without ischemia/reperfusion. Regional myocardial blood flow (RMBF) was measured with colored microspheres. Coronary vasoactive concentration of L-NAME and SMT depressed myocardial function as shown by decreased LVDP, dP/dt_max and coronary .ow before ischemia. After ischemia the recovery of the total CF was impaired in L-NAME and 50 μM SMT pretreated hearts which was related to homogenous RMBF decrease in the right and left ventricle compared to that in control group. Low concentration SMT (0.5 μM) showed no coronary vasoactive effects before ischemia and attenuated ischemia/reperfusion injury indicated by lower ischemic contracture at 25 min of ischemia and reduced CK and LDH release during reperfusion. Thus, NOS inhibition did not affect blood flow distribution in rat hearts either in the pre-ischemic or reperfusion period. Selective iNOS inhibition reduced ischemic injury by reducing ischemic contracture and CK as well as LDH release during reperfusion. Received: 20 March 2002, Returned for 1. revision: 8 April 2002, 1. Revision received: 14 August 2002, Returned for 2. revision: 5 September 2002, 2. Revision received: 3 February 2003, Accepted: 18 February 2003, Published online: 16 April 2003     

Brief ischemia-reperfusion performed after prolonged ischemia (ischemic postconditioning) can terminate reperfusion arrhythmias with no reduction of cardiac function in rats

OBJECTIVE: Recently, it has been reported that ischemic postconditioning, a brief episode of ischemia-reperfusion performed after prolonged ischemia, can reduce ischemic myocardial injury. However, the effects of ischemic postconditioning on ischemia/reperfusion injury remain unclear. We investigated the effects of brief ischemia-reperfusion before (ischemic preconditioning) and after (ischemic postconditioning) prolonged ischemia on myocardial ischemia/reperfusion injury, especially reperfusion arrhythmias. METHODS: Adult male Sprague-Dawley rats weighing about 400-500 g were used. The isolated heart was perfused using a working heart method (Krebs-Henseleit bicarbonate buffer). In the control group, after stabilization, diastolic global ischemia for 15 minutes was produced by a one-way ball valve with electrical pacing (330 bpm, 2.0 V). After ischemia, the heart was reperfused for 20 minutes. In the preconditioning and postconditioning groups, 5-minute global ischemia was produced before and after ischemia for 15 minutes with a 1 minute interval. An electrocardiogram was performed and left ventricular pressure (LVP, +dP/dt, -dP/dt) and CK activity in coronary effluent were measured during the protocol. RESULTS: Ischemic preconditioning did not affect the incidence or duration of reperfusion ventricular arrhythmias. Ischemic postconditioning could terminate reperfusion ventricular arrhythmias completely and reduced the duration of reperfusion ventricular arrhythmias significantly (P < 0.01). Furthermore, the recovery ratio of +dP/dt at 20 minutes after initial reperfusion was significantly higher in the postconditioning group than in the other groups. CONCLUSION: These results suggest that ischemic postconditioning can terminate reperfusion arrhythmias with no reduction of cardiac function, and may be useful for correcting stunned myocardium.     

Antioxidant UPF1 attenuates myocardial stunning in isolated rat hearts

Oxidative stress is a crucial pathophysiological mechanism of myocardial ischaemia-reperfusion injury (IRI). We evaluated the cardioprotective effects of a novel glutathione analogue, UPF1 (4-methoxy-L-tyrosinyl-gamma-L-glutamyl-L-cysteinyl-glycine; MW 483.5), on an isolated rat heart model of thirty-minute global ischaemia followed by 90 min of reperfusion. Treatment with UPF1 (1 mg/ml) prior to ischaemia improved the recovery of post-ischaemic left ventricular end-diastolic pressure (p=0.046), developed pressure (p=0.002) and coronary flow (p=0.01). No protective effect was observed when the hearts were treated with UPF1 after ischaemia. Administration of UPF1 had no influence upon infarct size or enzyme leakage from the heart. The results suggest that glutathione analogue type of biomolecules could possess a therapeutic potential in clinical situations where myocardial IRI is presented as myocardial stunning rather than tissue infarction.     

Local Inhibition of Angiotensin II Formation and Bradykinin Degradation in Isolated Hearts

ABSTRACT

The interaction of the converting enzyme (CE)-inhibitor ramipril and the bradykinin (BK)-antagonist D-Arg-[Hyp⁵,Thi^5,8,D-Phe⁷]BK with angiotensin I (ANG), ANG II and BK were studied in isolated hearts of rats and guinea pigs.

In isolated working rat hearts perfusion with ANG I and ANG II reduced cardiac function and coronary flow, increased the activities of lactate dehydrogenase (LDH) and creatine kinase (CK) in the perfusate, decreased high-energy rich phosphates and glycogen in the myocardium and increased duration and incidence of postischemic reperfusion arrhythmias. BK on the other hand reduced LDH and CK activities, improved metabolic parameters in the myocardium and reduced reperfusion arrhythmias.

In isolated rat hearts pretreatment with ramipril protected against reperfusion arrhythmias and reduced enzyme activities of LDH and CK in the coronary effluent. Cardiodynamic parameters and coronary flow improved and myocardial tissue levels of glycogen, ATP and creatine phosphate (CP) were elevated. Almost identical changes were seen during perfusion with BK. The cardioprotective effects produced by both, the CE-inhibitor and BK, were completely abolished when the BK-antagonist was added to the perfusate, while a smaller inhibition was obtained by indomethacin perfusion.

In isolated guinea pig hearts BK increased coronary flow. Single-dose oral pretreatment with ramipril potentiated, whereas perfusion with the BK-antagonist abolished this effect.

These data add support to the hypothesis that local inhibition of CE = kininase II contributes to the beneficial effects of CE-inhibitors in the heart.