L－精氨酸逆转一氧化氮抑制后的犬冠脉血流动力学改变和内皮素－1含量升高

观察了犬冠脉内灌注Ｎ－单甲基左旋精氨酸（Ｌ－ＮＭＭＡ）后再灌注Ｌ－精氨酸（Ｌ－Ａｒｇ）和单独灌注Ｌ－ＮＭＭＡ前后冠脉血流动力学、冠脉血流储备以及冠脉对不同浓度的乙酰胆碱（Ａｃｈ）反应的变化，同时用放免法测定冠脉前降支（ＬＡＤ）伴行静脉血中内皮素－１（ＥＴ－１）含量。结果发现，Ｌ－Ａｒｇ完全逆转了灌注Ｌ－ＮＭＭＡ引起的血流动力学改变，使心率回升，下降的基础冠脉流量（ＣＢＦ），从２０±８ｍｌ／ｍｉｎ回升至２８±７ｍｌ／ｍｉｎ，Ｐ＜０．０５)，降低的冠脉储备恢复，从５１±１０ｍｌ／ｍｉｎ升至９４±１５ｍｌ／ｍｉｎ，Ｐ〈０．０１)，ＥＴ－１的含量不再升高，从１５．５±３．０ｎｇ／Ｌ下降至５．０±２．０ｎｇ／Ｌ，Ｐ〈０．０１)，Ａｃｈ介导的ＣＢＦ增加不再受到抑制（Ｐ〈０．０１）。结果提示提供外源性Ｌ－Ａｒｇ可增加一氧化氮（ＮＯ）的产生，使由于ＮＯ抑制而产生的血流动力学改变和ＥＴ－１升高发生逆转。     

重型肝炎患者外周血内皮素及一氧化氮水平变化的意义

目的探讨内皮素（ＥＴ）和一氧化氮（ＮＯ）在重型肝炎（ＳＨ）发病中的作用．方法检测３０例ＳＨ,３２例慢性肝炎（ＣＨ）患者外周血ＥＴ和ＮＯ代谢物ＮＯ－２的水平,并用ＮＯ合成酶底物左旋精氨酸（ＬＡｒｇ）进行治疗前后对比．结果ＳＨ患者外周血ＥＴ和ＮＯ－２水平（１３９ｎｇ／Ｌ±１４ｎｇ／Ｌ,１２７μｍｏｌ／Ｌ±４０μｍｏｌ／Ｌ）明显高于ＣＨ组（８５ｎｇ／Ｌ±１５ｎｇ／Ｌ,６３μｍｏｌ／Ｌ±２５μｍｏｌ／Ｌ,Ｐ＜００１）．合并有Ⅲ,Ⅳ期肝性脑病与肝肾综合征患者外周血ＥＴ和ＮＯ－２水平（１４９ｎｇ／Ｌ±１３ｎｇ／Ｌ,１６２μｍｏｌ／Ｌ±３４μｍｏｌ／Ｌ）明显高于非肝性脑病患者（１１５ｎｇ／Ｌ±１２ｎｇ／Ｌ,８８μｍｏｌ／Ｌ±２４μｍｏｌ／Ｌ,Ｐ＜００１）和Ⅱ期肝性脑病患者（１３６ｎｇ／Ｌ±１０ｎｇ／Ｌ,１２２μｍｏｌ／Ｌ±２６μｍｏｌ／Ｌ,Ｐ＜００１）;ＬＡｒｇ静脉滴注后血浆ＥＴ水平和平均动脉压（ＭＡＰ）显著下降,而肌酐清除率（ｃＣｒ）和尿钠含量明显增加．结论ＥＴ和ＮＯ水平升高是引起ＳＨ多脏器功能障碍的重要因素．ＬＡｒｇ长期治疗可能促进ＳＨ患者脑水肿形成和肝肾综合征发生．     

一氧化氮、内皮素对冠脉血流动力学及内皮依赖性舒张功能影响的实验研究

在开胸麻醉犬心脏模型上分三组观察了冠状动脉（冠脉）内灌注内皮素（ＥＴ）、Ｎ－单甲基左旋精氨酸（Ｌ－ＮＭＭＡ）＋ＥＴ、Ｌ－ＮＭＭＡ前后各自不同的血流动力学和内皮依赖性舒张功能的改变．结果发现：灌注Ｌ－ＮＭＭＡ后，ＥＴ使静息冠脉血流量明显下降，主动脉压明显升高，冠脉储备明显下降，左室收缩压明显下降，左室舒张末压明显升高，乙酰胆碱不再使冠脉血流量增加（Ｐ＜０．０１），心电图ＳＴ段压低．提示内源性一氧化氮形成受抑制后，ＥＴ的血管收缩作用明显增加，并引起心肌舒缩功能和心电活动的改变．     

内皮素与一氧化氮在肝硬变血流动力学紊乱中的作用

目的研究内皮素、一氧化氮在肝硬变血流动力学紊乱中的作用及关系．方法应用放免法和高效液相色谱法分别检测肝硬变患者４４例，（男３２例，女１２例；年龄５０４岁±１１０岁），其中腹水患者２７例及健康对照２５例（男１８例，女７例；年龄４６８岁±１２４岁）血浆内皮素（ＥＴ）、一氧化氮（ＮＯ）及部分血管活性物质水平．结果肝硬变组血浆ＥＴ及ＮＯ水平（５７０ｎｇ／Ｌ±２５４ｎｇ／Ｌ，３８７２μｇ／Ｌ±１０６４μｇ／Ｌ）明显高于对照组（３３０ｎｇ／Ｌ±１０９ｎｇ／Ｌ，２９２３μｇ／Ｌ±５４５μｇ／Ｌ，Ｐ＜００１）．腹水患者血浆ＥＴ及ＮＯ水平（６７５ｎｇ／Ｌ±２４７ｎｇ／Ｌ，４１４７μｇ／Ｌ±１０７１μｇ／Ｌ），显著高于无腹水患者（４５９ｎｇ／Ｌ±１８３ｎｇ／Ｌ，３２７２μｇ／Ｌ±７０２μｇ／Ｌ，Ｐ＜００１）．ＮＯ与ＥＴ呈直线正相关（ｒ＝０７７２，Ｐ＜００１）．结论肝硬变患者ＥＴ与ＮＯ水平升高，且腹水患者较无腹水者更升高；两者呈直线正相关     

前列腺素E_1对风湿性二尖瓣病变合并肺动脉高压患者血液动力学的影响

应用漂浮导管监测前列腺素Ｅ１（ＰＧＥ１）对１１例以二尖瓣狭窄为主的风湿性心脏病合并肺动脉高压患者的体循环和肺循环的血液动力学作用。先以ＰＧＥ１２０ｎｇ·ｋｇ（－１）／ｍｉｎ静脉滴注１０分钟，再按患者情况每５～１０分钟增加５～１０ｎｇ·ｋｇ（－１）／ｍｉｎ。初剂量１０分钟时显著降低了平均肺动脉压（ＭＰＡＰ，Ｐ＜０．０１）、肺毛细血管楔压（ＰＣＷＰ，Ｐ＜０．０１）和右房压（ＲＡＰ，Ｐ＜０．０５）。剂量达３０．６±５．１ｎｇ·ｋｇ（－１）／ｍｉｎ维持１０及２０分钟时，ＭＰＡＰ、ＰＣＷＰ和ＲＡＰ等参数变化更显著；总外周阻力和肺血管阻力均显著降低（Ｐ＜０．０１），心脏指数显著增加（Ｐ＜０．０５），血压和心率的变化无显著性意义（Ｐ＞０．０５）。用药后，本组患者血液动力学异常基本被纠正，副作用轻微。提示ＰＧＥ１对风湿性心脏病二尖瓣狭窄为主的肺动脉高压患者有良好血液动力学效应。     

小剂量前列腺素E1对严重充血性心力衰竭及内皮素的影响

为探讨小剂量前列腺素Ｅ１（ＰＧＥ１）对重度充血性心力衰竭及内皮素（ＥＴ）水平的影响,对２０例经传统治疗无效的心衰患者小剂量静滴ＰＧＥ１１周,观察治疗前后临床症状、血流动力学及ＥＴ变化。结果发现,临床总有效率为９５％。肺动脉压（ＰＡＰ）、肺毛细血管嵌楔压（ＰＣＷＰ）比治疗前明显下降（４．９３±０．５３对４．００±０．５３ｋＰｓ,Ｐ＜０．０１;３．４７±０．５３对２．５３±０．４０ｋＰａ,Ｐ＜０．０１）,体循环阻力指数（ＳＶＲＩ）下降（２０４．８±２１．３对１５０．６±１．３ｋＰａ·ｓ·Ｌ－１·ｍ－２,Ｐ＜０．０５）,心指数（ＣＩ）上升（２．２±０．１对２．８±０．２Ｌ·ｍｉｎ－１·ｍ－２,Ｐ＜０．０５）。内皮素明显降低（１５４．５６±４．４０对１１８．１３±２．２４ｎｇ／Ｌ,Ｐ＜０．０１）。提示ＰＧＥ１可降低ＥＴ水平并通过多种机制对心衰产生有益的作用。     

病毒性肝炎和肝硬化患者IL－6、TNF－α的变化

为研究白细胞介素－６（ＩＬ－６）、肿瘤坏死因子（ＴＮＦ－α）在肝炎和肝硬化（ＬＣ）患者中的作用。检测了１５例正常人，１８例急性病毒性肝炎（ＡＨ），３７例慢性肝炎（ＣＨ），２０例ＬＣ患者血清及外周血单个核细胞（ＰＢＭＣ）的ＩＬ－６、ＴＮＦ－α水平。结果以ＣＨ患者ＩＬ－６、ＴＮＦ－α水平最高（血清及ＰＢＭＣ的ＩＬ－６水平分别为７２．１±３２．９４Ｕ／ｍｌ，１４０．７±３３．５Ｕ／ｍｌ；血清及ＰＢＭＣ的ＴＮＦ－α水平为３．９７±１．３８ｎｇ／ｍｌ，６．３５±１．４１ｎｇ／ｍｌ）。恢复期或稳定期ＴＮＦ－α和ＩＬ－６水平明显低于急性期或活动期（Ｐ＜０．０１）。ＣＨ患者肝组织学活动指数（ＨＡＩ）分数与ＰＢＭＣＩＬ－６和ＴＮＦ－α水平呈正相关（γ分别为０．８９，０．６８；Ｐ＜０．０５）。提示ＩＬ－６和ＴＮＦ－α是肝脏损害重要的炎症介质，介导肝细胞损害。     

间质性肺疾病患者血清和支气管肺泡灌洗液中内皮素1活性的变化

目的评价内皮素对肺纤维化发生、发展作用的影响。方法利用同位素放射免疫直接测定法,检测１０例肺结节病和８例特发性肺纤维化（ＩＰＦ）患者外周血和支气管肺泡灌洗液（ＢＡＬＦ）中内皮素１（ＥＴ１）的活性,并与８名健康非吸烟者进行对照。结果肺结节病和ＩＰＦ患者血清和ＢＡＬＦ中的ＥＴ１活性分别为（６２±２９）ｎｇ／Ｌ,（１７０±２４）ｎｇ／Ｌ和（７７±７１）ｎｇ／Ｌ、（１０±３）ｎｇ／Ｌ,与正常对照组（２０±８）ｎｇ／Ｌ、（４０±０６）ｎｇ／Ｌ比较,差异有显著性（Ｐ＜００１）;血清中ＥＴ１活性与动脉血氧分压（ＰａＯ２）呈明显负相关（ｒ＝－０５３８,Ｐ＜００１）;结节病组和ＩＰＦ组ＢＡＬＦ中的ＥＴ１水平与ＢＡＬＦ中细胞总数呈正相关（ｒ＝０６４９,Ｐ＜００１）,肺结节病患者、ＩＰＦ患者ＢＡＬＦ中ＥＴ１与淋巴细胞、中性粒细胞呈正相关（ｒ＝０７１２,０８１３,Ｐ均＜００１）。结论ＥＴ１在肺结节病和ＩＰＦ发病机制中起着重要作用,并可作为疾病活动性判定的一项重要参考指标。     

高血压患者血浆和淋巴细胞中血管紧张素Ⅱ、内皮素和一氧化氮的变化及关系

分析一组高血压病患者血浆和淋巴细胞中血管紧张素Ⅱ（ＡｎｇⅡ）、内皮素（ＥＴ）和一氧化氮（ＮＯ）含量的变化及它们间的相互关系。方法高血压（ＥＨ）组３９例，正常对照（ＮＣ）组４１例，放射免疫分析法测定ＡｎｇⅡ、ＥＴ，高效液相色谱分析法测定ＮＯ。结果ＥＨ患者血浆和淋巴细胞中ＥＴ均高于ＮＣ组（Ｐ分别＜０．０５和＜０．０１），ＮＯ低于ＮＣ组（Ｐ分别＜０．０５和＜０．０１）。除血浆ＥＴ和ＮＯ外，各指标改变ＥＨⅡ期较Ⅰ期明显（Ｐ分别＜０．０５和＜０．０１）。逐步回归分析表明，ＥＨ组平均动脉压（ＭＡＰ）与血浆及淋巴细胞中ＡｎｇⅡ、ＥＴ呈正相关，与ＮＯ负相关（ｒ分别＝０．６７，０．８１，Ｐ均＜０．０１）；ＥＨ组血浆和淋巴细胞中ＮＯ与ＡｎｇⅡ、ＥＴ均呈负相关（ｒ分别＝－０．６５１，－０．７２５，Ｐ均＜０．０１）。结论淋巴细胞反映血管内皮细胞内分泌功能比血浆更为敏感，与ＭＡＰ相关性更好，ＡｎｇⅡ、ＥＴ和ＮＯ三者分泌失平衡，是ＥＨ发病的重要原因之一。     

肝硬变血浆内毒素与一氧化氮水平的改变及关系的研究

目的研究肝硬变患者血浆内毒素与一氧化氮水平改变及关系．方法应用鲎试剂定量法和高效液相色谱分析法分别检测肝硬变患者４４例（男３２例，女１２例；年龄２５岁～７３岁，平均５０４岁±１１０岁）；ＣｈｉｌｄＰｕｇｈＡ级９例，Ｂ级２０例，Ｃ级１５例；其中有腹水者２７例及健康对照２５例（男１８例，女７例，年龄２４岁～６３岁，平均４６８岁±１２４岁）血浆内毒素和一氧化氮水平．结果肝硬变血浆内毒素及一氧化氮水平（２３７１ＥＵ／Ｌ±８２３ＥＵ／Ｌ，３８７１７ｎｇ／ｍｌ±１０６４１ｎｇ／ｍｌ）明显高于对照组（１５６７ＥＵ／Ｌ±２４６ＥＵ／Ｌ，２９２３０ｎｇ／ｍｌ±５４４９ｎｇ／ｍｌ，Ｐ＜００１）．腹水患者内毒素与一氧化氮水平（２３６９ＥＵ／Ｌ±５３６ＥＵ／Ｌ，４１４６７ｎｇ／ｍｌ±１０７０５ｎｇ／ｍｌ）明显高于无腹水者（１９６９ＥＵ／Ｌ±４５２ＥＵ／Ｌ，３２７１７ｎｇ／ｍｌ±７０２０ｎｇ／ｍｌ，Ｐ＜００５，Ｐ＜００１）．一氧化氮与内毒素呈直线正相关（Ｐ＜００１，ｒ＝０７８２）．结论肝硬变患者血浆内毒素及一氧化氮水平皆升高，且两者呈直线正相关．     

Effects of inhibition of nitric oxide formation on the regulation of coronary blood flow in anesthetized dogs

In 11 open-chest dogs with a flowmeter on the left circumflex artery, L-NMMA, a selective inhibitor of nitric oxide-formation, was subselectively infused into the left circumflex artery at a rate of 2.5mg/ml (ml/min) to avoid systemic hemodynamic effects. The coronary blood flow at normal arterial blood pressure was similar prior to and during L-NMMA infusion. However, when the arterial blood pressure was raised by inflating a balloon in the descending aorta, the nitric oxide suppression induced a dramatic increase in coronary vascular resistance by almost 40% compared to control conditions without L-NMMA infusion at identically elevated arterial blood pressure. L-NMMA induced a significant downward shift and flattening of the pressure-flow relation over a pressure range from 60–150 mmHg. Peak hyperemic coronary flow after 20-s transient coronary occlusion was similar prior to and during L-NMMA infusion, but the duration of the hyperemic flow response was significantly shortened during L-NMMA infusion indicating exaggerated constriction after hyperemic stimulus. The EDRF/nitric oxide-system plays an important role for the regulation of coronary blood flow by counteracting autoregulatory constrictor responses to increased driving pressure and shear stress in the intact canine circulation.Supported in part by grant 1 RO1 HL-40865 from the National Heart, Lung, and Blood Institute. U.S. is the recipient of research grant So 241/1-1 from the Deutsche Forschungsgemeinschaft     

Leptin causes nitric-oxide independent coronary artery vasodilation in humans.

Recent studies have shown that leptin causes vasodilation. However, it is unclear whether leptin causes coronary vasodilation in humans. To determine how leptin affects human coronary arteries and whether endothelium-derived nitric oxide (EDNO) is involved in the coronary arterial response to leptin, we infused leptin (0.3, 3 and 30 ng/kg/min) for 2 min into the left coronary ostium before and after an infusion of nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), in 11 men with angiographically normal coronary arteries. The diameter of the epicardial coronary arteries was quantitatively measured, and coronary blood flow (CBF) was calculated by quantitative angiography and Doppler flow velocity measurements. The changes in these parameters in response to leptin are expressed as the % change from the baseline values. Leptin caused coronary dilation (0.3 ng/kg/min: 2.0+/-0.5%; 3 ng/kg/min: 4.9+/-0.7%; 30 ng/kg/min: 3.8+/-0.9%) and increased CBF (13.6+/-3.3%, 36.8+/-5.6%, and 39.2+/-7.4%, respectively). After the infusion of L-NMMA, leptin also caused coronary dilation (2.0+/-0.4%, 4.5+/-0.7%, and 4.6+/-0.8%, respectively) and increased CBF (14.6+/-2.8%, 39.2+/-5.7%, 40.3+/-6.2%, respectively). Leptin-induced coronary vasodilation was not affected by the infusion of L-NMMA. These results suggest that leptin dilates coronary arteries in humans. Furthermore, EDNO may not contribute to leptin-induced coronary dilation.     

Normalization of impaired coronary circulation in hypertrophied rat hearts

We tested the hypothesis that impaired coronary autoregulation, decreased flow reserve, and diminished reactive hyperemic response in hypertrophied hearts with coronary arterial hypertension may be reversible after relief of pressure overload. In 4-week ascending aortic banded rats, in vivo peak systolic left ventricular pressure increased to 178 +/- 8 mm Hg (103 +/- 6 mm Hg in sham-operated control group). This increased pressure produced myocardial hypertrophy, and the left ventricular weight/body weight ratio was 46% above that of the control group. After the rats were killed, the coronary perfusion pressure-flow relations were obtained during resting conditions and maximal vasodilation after a 40-second period of ischemia in beating but nonworking isolated hearts perfused with Tyrode's solution with bovine red blood cells and albumin. In hearts from control rats, coronary autoregulation (i.e., a slight decrease in flow with reduction of pressure) was observed in the range of 50-100 mm Hg of perfusion pressure. A pronounced reactive hyperemic response was observed: a peak flow/resting flow ratio of 2.9 +/- 0.1 and a repayment ratio of 1.7 +/- 0.2 at 100 mm Hg of perfusion pressure. In hearts of banded rats the resting pressure-flow relation was rectilinear in the range of 25-175 mm Hg of perfusion pressure. Flow reserve and the time of reactive hyperemia to one half peak flow decreased at 50, 100, and 150 mm Hg of perfusion pressure compared with values in control rat hearts. Four weeks after debanding, peak systolic left ventricular pressure and cardiac hypertrophy had normalized. The impaired autoregulation, decreased flow reserve, and diminished reactive hyperemic response had completely reversed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of dietary L-arginine on the reactivity of canine coronary arteries

Experiments were designed to determine the effects of supplemental dietary L-arginine on the endothelial and smooth muscle function of canine coronary arteries. One group of dogs was fed the standard laboratory chow while another group was supplemented with 250 mg/kg per day L-arginine. All dogs had undergone bilateral reversed interposition saphenous vein grafting and received 325 mg/day oral aspirin. After 5 weeks of arginine feeding, left circumflex coronary arteries were removed, cut into rings, and suspended for the measurement of isometric force in organ chambers. Concentration-response curves were obtained to L-arginine, UK-14,304 (alpha2-adrenergic agonist) and A23187 (calcium ionophore) in the absence and presence of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium (TEA) alone or in combination. Serum concentrations of L-arginine increased by about 20% following 2 weeks of arginine feeding and remained elevated throughout the study. In rings with and without endothelium contracted with prostaglandin F2alpha, L-arginine caused concentration-dependent contractions in rings from control animals but no significant change in tension in rings from arginine-fed animals. Contractions to L-arginine in control animals were reduced by either L-NMMA or TEA. Endothelium-dependent relaxations to the alpha2-adrenergic agonist were decreased with arginine feeding while relaxations to the calcium ionophore and the endothelium-derived factor nitric oxide were similar among groups. Relaxations to UK-14,304 were reduced by L-NMMA in both groups but by TEA only in rings from control animals. These results suggest that dietary supplementation with L-arginine modifies reactivity of endothelium and smooth muscle by at least two mechanisms: one associated with activation of potassium channels and the other with receptor-coupled release of nitric oxide.     

Nitric Oxide Contributes to Vasomotor Tone in Hypertensive African Americans Treated With Nebivolol and Metoprolol

Endothelial dysfunction is more prevalent in African Americans (AAs) compared with whites. The authors hypothesized that nebivolol, a selective β₁‐antagonist that stimulates nitric oxide (NO), will improve endothelial function in AAs with hypertension when compared with metoprolol. In a double‐blind, randomized, crossover study, 19 AA hypertensive patients were randomized to a 12‐week treatment period with either nebivolol 10 mg or metoprolol succinate 100 mg daily. Forearm blood flow (FBF) was measured using plethysmography at rest and after intra‐arterial infusion of acetylcholine and sodium nitroprusside to estimate endothelium‐dependent and independent vasodilation, respectively. Physiologic vasodilation was assessed during hand‐grip exercise. Measurements were repeated after NO blockade with L‐N^G‐monomethylarginine (L‐NMMA) and after inhibition of endothelium‐derived hyperpolarizing factor (EDHF) with tetraethylammonium chloride (TEA). NO blockade with L‐NMMA produced a trend toward greater vasoconstriction during nebivolol compared with metoprolol treatment (21% vs 12% reduction in FBF, P=.06, respectively). This difference was more significant after combined administration of L‐NMMA and TEA (P<.001). Similarly, there was a contribution of NO to exercise‐induced vasodilation during nebivolol but not during metoprolol treatment. There were significantly greater contributions of NO and EDHF to resting vasodilator tone and of NO to exercise‐induced vasodilation with nebivolol compared with metoprolol in AAs with hypertension.     

The value of lesion cross-sectional area determined by quantitative coronary angiography in assessing the physiologic significance of proximal left anterior descending coronary arterial stenoses

The results of previous work from this laboratory have shown a poor correlation between percent stenosis (determined visually with calipers) and the coronary reactive hyperemic response (an index of maximal coronary vasodilator capacity) determined during cardiac surgery. This study was performed to determine whether other parameters of lesion severity could predict the reactive hyperemic response and thus the hemodynamic significance of coronary stenoses in human beings. Twenty-three patients with lesions in the proximal left anterior descending coronary artery were studied. To account for differences in expected vessel size, patients with large diagonal branches (greater than one-half the diameter of the left anterior descending artery) arising before the lesion were excluded. Computer-assisted quantitative coronary angiography was used to measure percent diameter stenosis, percent area stenosis, and minimal stenosis cross-sectional area. With a pulsed Doppler velocity probe, reactive hyperemic responses were recorded after a 20 sec coronary occlusion of the left anterior descending artery at cardiac surgery before cardiopulmonary bypass and were quantified by the peak/resting velocity ratio (normal greater than 3.5:1). Percent area stenosis ranged from 7% to 54% for vessels with normal reactive hyperemic responses and from 27% to 94% for vessels with abnormal reactive hyperemic responses. With both percent diameter stenosis and percent area stenosis there was substantial overlap between vessels with normal and abnormal reactive hyperemic responses. In contrast, nine of nine vessels with normal reactive hyperemic responses had lesion minimal cross-sectional areas of greater than 3.5 mm2 and 13 of 14 vessels with abnormal reactive hyperemic responses had minimal cross-sectional areas of less than 3.5 mm2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dietary arginine prevents atherogenesis in the coronary artery of the hypercholesterolemic rabbit

Objectives. This study was designed to test the hypothesis that long-term oral supplementation of dietary l-arginine (to provide a sustained elevation of nitric oxide activity) would inhibit atherogenesis in hypercholesterolemic rabbits, as assessed by histomorphometric measurements.Background. Endothelium-derived nitric oxide inhibits a number of processes that are critical in atherogenesis. Hypercholesterolemia reduces endothelial nitric oxide activity, and we postulate that this may promote atherogenesis. This reduction in nitric oxide activity can be reversed acutely by intravenous infusion of l-arginine, the precursor of nitric oxide. We show that dietary supplementation of l-arginine abrogates the development of coronary atheroma in hypercholesterolemic rabbits.Methods. Male New Zealand White rabbits were fed normal rabbit chow, 1% cholesterol chow or 1% cholesterol chow with dietary arginine or methionine supplementation to increase their intake of these amino acids sixfold. After 1 or 10 weeks of dietary intervention, the left main and left anterior descending coronary arteries were harvested for histologic study. Plasma cholesterol measurements were elevated to the same degree in all groups of rabbits receiving the 1% cholesterol diet, whereas plasma arginine levels were doubled in the arginine-treated group. High density lipoprotein (HDL) cholesterol values were not affected by arginine treatment.Results. In rabbits receiving the 1% cholesterol diet, with or without methionine supplementation, light and electron microscopy revealed a marked increase from 1 to 10 weeks in the intimal accumulation of macrophages, associated with an increase in the intimal area of the left main coronary artery. By contrast, in arginine-treated hypercholesterolemic rabbits, there was a near absence of adherent monocytes and tissue macrophages and no progression of intimal thickness from 1 to 10 weeks.Conclusions. Dietary supplements of l-arginine prevent intimal thickening in the coronary arteries of hypercholesterolemic rabbits. This antiatherogenic effect is not due to an alteration in plasma total cholesterol, HDL cholesterol or caloric or nitrogen balance. The data are consistent with the hypothesis that nitric oxide has antiatherogenic properties.     

Effect of acute cardiac lymph stasis on metabolic coronary adaptation in the dog

Surgical blockade of cardiac lymph drainage was performed in dogs to examine the effect of acute cardiac lymph stasis on coronary adaptive mechanisms. Coronary blood flow (CBF) was measured using an electromagnetic flow probe on the left anterior descending (LAD) artery. Metabolic autoregulatory capacity was assessed by eliciting reactive hyperemic responses after flow interruptions of 10-60 second duration and by administering submaximal doses (250-500 micrograms) of adenosine, the putative transmitter of reactive hyperemia, into the left heart. The effect of lymph stasis was tested in two experimental groups, one hour and 48 hours after lymph obstruction and the data compared to control dogs. Although cardiac lymph stasis did not notably affect baseline arterial pressure and CBF, both reactive hyperemic response and adenosine-induced coronary vasodilation were reduced significantly (equal to or less than 50% control). On occasion, a complete absence of autoregulation was observed. These findings suggest that cardiac lymph stasis decreases vascular responsiveness to physiologic vasodilator stimuli and/or retards diffusion of biologically unstable substance(s) presumably involved in autoregulation. Persistently impaired coronary autoregulation in the lymphedematous heart may contribute to progressive ischemic damage as for example after myocardial infarction.     

The contribution of nitric oxide to exercise hyperemia in the human forearm

The contribution of nitric oxide (NO) to exercise-induced hyperemia is debated. Previous conclusions that nitric oxide synthase (NOS) inhibition reduces endothelium-dependent vasodilation during exercise hyperemia may be confounded by inhibitor-mediated increases in resting vascular tone. In this study, nine healthy participants performed wrist flexion exercise before and during intra-arterial administration of the NOS-inhibitor NG-monomethyl-L-arginine (L-NMMA, 2 mg x min(-1)). Nine additional subjects performed this procedure while nitroprusside (0.2 microg x min(-1)) was co-infused with L-NMMA to maintain basal flow. Forearm blood flow was assessed with venous occlusion strain-gauge plethysmography at baseline, immediately after cessation of exercise, and continuously for 5 minutes thereafter. L-NMMA alone reduced resting flow by 26%, peak flow immediately after exercise by 20%, and integrated post-exercise hyperemic volume by 50% (all p < 0.05). Stabilization of resting vasodilator tone by nitroprusside eliminated the effects of L-NMMA on peak flow after exercise, yet L-NMMA still attenuated total hyperemic volume. In a time-control study of 12 subjects, there was no change in peak blood flow or hyperemic volume. This study indicates that NO is not a major regulator of peak limb blood flow measured immediately after cessation of dynamic exercise. The contribution of NO to exercise hyperemia is limited to the recovery period after exercise.     

The effect of coronary flow restriction on the viability of porcine myocardium

Summary The effect of a prolonged (3 hours) defined coronary flow restriction on early (30 minutes) and late (24 hours) reperfusability and survival of the myocardium was studied in a closed-chest pig model. Coronary blood flow (CBF) was restricted to 51±4% (moderate flow restriction) and 36±6% (severe flow restriction) of preexisting resting flow values. Regional determination of the restricted CBF after severe flow restriction showed the anticipated extension of the ischemic area from endocardial to epicardial layers and to the lateral border zone. Upon early reperfusion a hyperemic effect was observed, which reflected the preceding degree of underperfusion. The maximal hyperemic effect was found in samples with CBF restriction to 38% of the control flow values. Twenty-four hours after blood flow restitution the hyperemic effect had disappeared. At this time control flow values had not returned, where previous CBF restriction had exceeded 50%. The amount of infarcted tissue in the area supplied by the left circumflex artery was 5.7% after moderate, and 31.6% after severe flow restriction. Morphologically the infarcted myocardium consisted of disseminated necrosis after moderate, and of confluent necrosis after severe flow restriction. At flow restriction exceeding 50%, the chances of reestablishing perfusion and thus salvaging the myocardium appear minimal.This study was supported by the Deutsche Forschungsgemeinschaft-Grant Bo 172/7