内源性NO在内毒素引起的PAH和肺损伤中的作用

内源性ＮＯ在内毒素引起的ＰＡＨ和肺损伤中的作用河北医科大学病理生理教研室（石家庄０５００１７）万梅凌亦凌谷振勇实验观察了静脉预注入ＮＯ合成酶（ＮＯｓｙｎｔｈａｓｅ，ＮＯＳ）抑制剂Ｎω硝基左旋精氨酸（Ｎω－ｎｉｔｒｏ－Ｌ－ａｒｇｉｎｉｎｅ，Ｌ－ＮＮＡ...     

NO—样舒血管因子在大鼠腹膜炎败血症中的作用

为探讨ＮＯ样舒血管因子（ＮＯ－ＬＲＦ）在腹膜炎败血症中的作用及其病理生理意义，本工作在大鼠腹膜炎败血症模型上，发现早、晚期败血症大鼠的离体主动脉环对去甲肾上腺素的反应降低；血管组织ｃＧＭＰ含量增加，表明败血症动物Ｌ－Ａｒｇ／ＮＯ途经增强，用ＮＯ合成前体Ｌ－精氨酸（Ｌ－Ａｒｇ）或ＮＯ合成抑制剂ＮＧ－ｎｉｔｒｏ－Ｌ－ａｒｇｉｎｉｎｅ（Ｌ－ＮＮＡ）、可溶性鸟苷酸环化酶抑制剂亚甲蓝灌流，分别增加或降低败血     

NO－样舒血管因子在大鼠腹膜炎败血症中的作用

为探讨ＮＯ样舒血管因子（ＮＯ－ＬＲＦ）在腹膜炎败血症中的作用及其病理生理意义，本工作在大鼠腹膜炎败血症模型上，发现早、晚期败血症大鼠的离体主动脉环对去甲肾上腺素的反应降低；血管组织ｃＧＭＰ含量增加，表明败血症动物Ｌ－Ａｒｇ／ＮＯ途经增强，用ＮＯ合成前体Ｌ－精氨酸（Ｌ－Ａｒｇ）或ＮＯ合成抑制剂ＮＧ－ｎｉｔｒｏ－Ｌ－ａｒｇｉｎｉｎｅ（Ｌ－ＮＮＡ）、可溶性鸟苷酸环化酶抑制剂亚甲蓝灌流，分别增加或降低败血症动物主动脉的上述变化，但上述药物的作用不依赖于血管内皮的存在，提示败血症动物主要为非内皮源性ＮＯ－ＬＲＦ增强。整体实验发现：Ｌ－Ａｒｇ可明显改善而Ｌ－ＮＮＡ却恶化休克过程，提示ＮＯ－ＬＲＦ可能参与败血症休克时机体的适应性保护机制。     

多形核白细胞在内毒素休克时肝组织损伤中的作用

家兔输注内毒素０．３ｍｇ／ｋｇ复制内毒素休克模型。输注４ｈｒ以后ＰＭＮ吞噬发光和Ｏ＾－２生成呈持续升高（Ｐ＜０．０５～０．０１），同时激活的ＰＭＮ释放氧自由基损伤肝细胞，引起肝细胞内ＭＤＡ含量和培养上清ＬＤＨ活性升高（Ｐ＞０．０５～０．０１）。体外内毒素与ＰＭＮ共孵，ＰＭＮ吞噬发光和Ｏ＾－２生成呈先升高后回降的变化，经内毒素在体外激活的ＰＭＮ也能明显引起肝细胞内ＭＤＡ含量和上清ＬＤＨ活性升高（Ｐ＜     

一氧化氮在培养的大鼠心肌细胞缺氧—复氧损伤中的作用

目的：观察一氧化氮（ＮＯ）对心肌细胞缺氧－复氧损伤（ＨＲＩ）的作用。方法：培养的大鼠心肌细胞，培养液中分别预先加入ＮＯ前体Ｌ－精氨酸（Ｌ－Ａｒｇ）、ＮＯ供体ＳＩＮ－１或硝普钠（ＳＮＰ）、ＮＯＳ抑制剂Ｌ－ＮＮＡ或ＮＯＳ诱导剂脂多糖（ＬＰＳ），经缺氧１２０ｍｉｎ，复氧６０ｍｉｎ处理后，检测细胞存活率，乳酸脱氢酶（ＬＤＨ）漏出量，亚硝酸盐（ＮＯ２）含量及细胞诱导型ＮＯ合酶（ｉＮＯＳ）活性等指标的改变。结果：①与常氧组比较，缺氧－复氧ＨＲ降低细胞存活率（２３％，Ｐ＜０．０１），增加ＬＤＨ漏出（６２倍，Ｐ＜０．０１），ｉＮＯＳ活性（７７％，Ｐ＜０．０１），ＮＯ２含量（６１７％，Ｐ＜０．０１）。②ＨＲ前预先加入ＳＩＮ－１、ＳＮＰ或Ｌ－Ａｒｇ，均引起ＬＤＨ漏出进一步增高（Ｐ＜０．０１），细胞存活率进一步降低（Ｐ＜０．０１或Ｐ＜０．０５）。③Ｌ－ＮＮＡ２ｍｍｏｌ／Ｌ，单独应用对细胞损伤的影响无统计学意义，与Ｌ－Ａｒｇ联合应用，则减弱Ｌ－Ａｒｇ的细胞损伤作用。④ＬＰＳ１μｇ／ｍＬ，增加ｉＮＯＳ活性（２６倍，Ｐ＜０．０１）和ＬＤＨ漏出（５６％，Ｐ＜０．０１）。结论：ＮＯ加重心肌细胞ＨＲＩ，是心肌细胞ＨＲＩ的损伤因子     

白细胞介素8和一氧化氮在家兔内毒素性急性肺损伤中的作用

目的和方法：采用间隔２４ｈ两次注射大肠杆菌内毒素（ＥＴ）的方法，复制家兔内毒素性急性肺损伤模型，探讨肺损伤的机理。结果：ＥＴ组血浆、肺组织匀浆及支气肺泡灌洗液（ＢＡＬＦ）中白细胞介素８（ＩＬ－８）、亚硝酸／硝酸根离子（ＮＯ２－／ＮＯ３－）水平显著增高（Ｐ＜００１），血浆补体Ｃ５ａ活性明显增高（Ｐ＜００１），ＢＡＬＦ内中性粒细胞明显增多，肺系数、肺水含量及通透指数升高。ＩＬ－８、ＮＯ２－／ＮＯ３－水平以及血清和ＢＡＬＦ中酸性磷酸酶活性变化高度相关。结论：ＩＬ－８、一氧化氮（ＮＯ）参与内毒素性急性肺损伤，而ＩＬ－８是造成肺损伤的重要中间环节。     

一氧化氮在实验性肝损伤中的作用

目的：观察３种细胞因子对体外培养大鼠肝细胞产生一氧化氮（ＮＯ）的影响及ＮＯ在实验性肝损伤中的作用。方法与结果：给大鼠注射内毒素后分离肝细胞,培养液中加入细胞因子（γ－ＩＦＮ,ＩＬ－２,ＴＮＦ－α）,上清液中ＮＯ含量增加,两种以上细胞因子联合应用,ＮＯ含量增加更明显;大鼠注射内毒素及Ｌ－精氨酸,血清中ＮＯ含量增加,肝损伤减轻;大鼠给硫代乙酰胺（ＴＡＡ）灌胃,并注射ＮＯ生成抑制剂Ｌ－ＮＮＡ,动物出现嗜     

一氧化氮在大鼠创伤局部微循环灌流减少中的作用

目的和方法：用激光多普勒微循环血流仪测定大鼠断肢局部微循环血液灌流量，用比色法测定血浆亚硝酸盐（ＮＯ２－）水平间接反映血浆一氧化氮（ＮＯ）含量。结果：（１）断肢局部微循环血液灌流量在断肢Ｏ、１、２和３ｈ均明显下降，局部股静脉血浆ＮＯ２－含量在断肢２、３ｈ显著降低，断肢２、３ｈ局部股静脉血浆ＮＯ２－水平与局部微循环血液灌流量呈显著正相关。（２）ＮＯ合成底物左旋精氨酸（Ｌ－Ａｒｇ）能改善断肢２、３ｈ的局部微循环血液灌流量，一氧化氮合成抑制剂左旋单甲基精氨酸（Ｌ－ＮＭＡ），可抑制此作用。（３）断肢３ｈ局部股静脉血浆ＮＯ２－水平Ｌ－Ａｒｇ组明显高于生理盐水（ＮＳ）组（Ｐ＜００５），Ｌ－Ａｒｇ合用Ｌ－ＮＭＡ组则明显低于ＮＳ组（Ｐ＜００５）。结论：断肢创伤通过内源性Ｌ－Ａｒｇ－ＮＯ通路而降低ＮＯ生成，参与断肢局部２、３ｈ的血管痉挛和微循环血液灌流量下降     

一氧化氮合酶阻断剂对豚鼠耳蜗基底膜振动速度的影响

目的：观察Ｎ－甲基－左旋精氨酸（ＮＮＡ）对基底膜振动速度（ＢＭＶ）的影响,了解一氧化氮（ＮＯ）对耳蜗外毛细胞（ＣＯＨＣｓ）的作用。方法：杂色豚鼠２５只,麻醉、手术准备后用１．６ｍｍｏｌ／Ｌ的Ｌ－ＮＮＡ８μＬ行耳蜗底圈鼓阶内灌注,测试ＢＭＶ、听神经复合动作电位（ｃＡＰ）、蜗内电位（ＥＰ）,记录用直流电脉冲诱发的ＢＭＶ。结果：蜗内灌注Ｌ－ＮＮＡ后,ＢＭＶ大约提高了３倍,耳蜗微音器电位振幅略有下降,而Ｅ     

内皮源性舒张因子在甘油致大鼠急性肾功能衰竭中的作用

为探讨内皮源性舒血管因子（ｅｎｄｏｔｈｅｌｉｕｍ－ｄｅｒｉｖｅｄｒｅｌａｘｉｎｇｆａｃｔｏｒ，ＥＤＲＦ）在急性肾功能衰竭（ＡＲＦ）发生发展中的作用及其机制，在甘油致大鼠ＡＲＦ模型上，分别观察了ＮＯ前体Ｌ－ａｒｇｉｎｉｎｅ（Ｌ－Ａｒｇ）和ＮＯ合成酶抑制剂Ｎ－ｎｉｔｒｏ－Ｌ－ａｒｇｉｎｉｎｅ（Ｌ－ＮＮＡ）的作用。实验结果表明：ＡＲＦ大鼠ＮＯ合成减少，Ｌ－Ａｒｇ能明显降低ＡＲＦ大鼠血清中的ＢＵＮ和Ｓｃｒ，尿中ＮＡＧ和肾皮质中的钙含量，而提高血清ＮＯ水平，增加肾组织ｃＧＭＰ含量，改善肾功能；Ｌ－ＮＮＡ则使ＡＲＦ恶化。提示：ＥＤＲＦ在甘油所致ＡＲＦ大鼠的发生发展中可能起重要的保护作用。     

中脑导水管周围灰质微量注射N-硝基左旋精氨酸和硝普钠对大鼠血压的影响

目的　研究中脑导水管周围灰质 (PAG)内NO对血压的作用。方法　采用PAG微量注射N 硝基左旋精氨酸和硝普钠 ,观察大鼠血压的变化。结果　PAG微量注射N 硝荃左旋精氨酸 (L NNA)后 ,平均动脉压 (MAP)显著升高 ,此效应可被预先注射L Arg逆转。PAG微量注射硝普钠 (SNP)后 ,MAP显著降低 ,此效应可被预先注射荷包丹碱 (Bic)递转。结论　PAG内L Arg NO通路对动物血压有紧张性抑制作用 ,可能是通过GABA受体介导。     

Role of nitric oxide in the gastro-protective effect of lithium.

Background and aim: Lithium is widely used for the management of neuropsychiatric symptoms in bipolar disorders. A few studies have shown that lithium has a protective effect against gastric damage with an unknown mechanism. Some of the actions of lithium are mediated through nitric oxide (NO), which has an important role in the regulation of gastric wall blood flow as well as gastric mucosal integrity. The aim of this study was to test the hypothesis if the gastro-protective effect of lithium is mediated through NO. Methods: Male Wistar rats were pre-treated with either a non-selective NO synthase inhibitor (N(G)-nitro-l-arginine, 10mg/kg), a selective inducible NO synthase inhibitor (aminoguanidine, 100mg/kg) or saline. Lithium carbonate (10, 20, 50 and 100mg/kg) was then administered intraperitoneally 1h before the induction of gastric mucosal damage. Gastric damage was induced by either water immersion stress or ethanol gavage in rats. Results: Lithium had a significant protective effect in both stress and ethanol-induced gastric damage, but it needed in ethanol-induced gastric damage a higher dose than in the stress induced lesion. Lithium carbonate doses 20 and 50mg/kg produced plasma concentrations that were in the range of human therapeutic Li levels (0.6-1.0muM). Pre-treatment of animals with N(G)-nitro-l-arginine (20 and 40mg/kg) reduced the protective effect of lithium against ethanol-induced gastric damage, but not in stress-induced damage. Aminoguanidine administration showed no effect on the damage reduction either in control or lithium treated rats. Conclusions: The results indicate that NO might play a role in the gastro-protective effect of lithium against ethanol-induced gastric damage in rats.     

一氧化氮对烧伤休克大鼠微循环的作用

一氧化氮对烧伤休克大鼠微循环的作用石胜军＊吴坤莹＊一氧化氮（ＮＯ）是近年来发现的一种新的信息分子，已知其与多种生理和病理状态的调节有密切关系［１］。在烧伤休克研究中，已证实大鼠烫伤后尿中ＮＯ的稳定终产物ＮＯ－２／ＮＯ－３的量明显升高［２］；但ＮＯ在烧...     

Clenbuterol induces expression of multiple myosin heavy chain isoforms in rat soleus fibres

Uterine secretory cells receive a sympathetic cholinergic secremotor innervation. Nitric oxide (NO) has been suggested to be a second messenger of neurogenic modulated glandular secretion of the seminal vesicle. Thus a similar pattern for nervous induced carbohydrate secretion of the endometrium was assumed. The nitric oxide synthase (NOS) activity was estimated via formation of L ‐citrulline from L ‐arginine and histochemically with the nicotinamide‐adenine dinucleotide phosphate diaphorase (NADPH‐d) nitro blue technique. The carbohydrate secretion from everted uterine horns placed in organ baths was estimated. A calcium dependent formation of citrulline was found in the uterine horn suggesting an NOS activity. Strong NADPH staining cells were found in the glandular ducts of the endometrium and in the epithelial linings of the oviduct. Carbachol induced carbohydrate secretion of the endometrium while N‐nitro L ‐arginin (L ‐NNA) and N‐nitro L ‐arginin methyl ester (L ‐NAME) inhibited the carbachol induced secretion. The isomer D ‐NAME had no effect on carbachol induced secretion. When L ‐arginine was administered together with L ‐NNA no inhibitory effect on carbachol induced secretion was seen. L ‐arginine only had no effect on carbohydrate secretion. The NO donor glyceryl tritrate increased carbohydrate secretion but no synergistic effect was seen in combination with carbachol. The results suggest that glandular NO production is a prerequisite for muscarinic carbohydrate secretion of the endometrium.     

Inhibition of nitric oxide synthase induces intestinal mucosaldamage and increases mortality in rats treated by FK506

INTRODUCTION: Despite the beneficial immunosuppressive effects of FK506 during small intestine transplantation, FK506 appears to have direct toxic effects on the intestine. The mechanisms of FK506-induced intestinal damage is unclear, and whether nitric oxide (NO) is involved in the mechanism has not been well defined. This study was designed to evaluate the effects of NG-Nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, on small intestinal damage in rats treated with FK506. MATERIALS AND METHODS: Wistar rats weighing 240-260 g, aged 11 weeks, were administered FK506 (5 mg/kg/day i.m) and/or L-NAME (5 mg/dl in drinking water) for 10 days. Body weight gain, diarrhoea and mortality were observed during experiment. At the end of experiment, the intestinal specimens were excised for histological evaluation. In addition, the effects of L-aginine treatment (1 g/dl in drinking water) were evaluated in this study. RESULTS: L-NAME administration time-dependently induced diarrhoea and high mortality in the rats treated with FK506. At the end of 10 days treatment, 7 of 12 rats (58.3%) suffered from diarrhoea and 5 of 12 rats (41.7%) died in the FK506 + L-NAME group (vs. FK506 group, p = 0.05). A significant loss of body weight was also found in the rats treated with FK506 + L-NAME (-52.2 +/- 28.8 g, in FK506 + L-NAME group vs. -14.3 +/- 8.7 g in FK506 group, p = 0.001). In parallel with the severe diarrhoea and high mortality, the loss of villi, hemorrhage and necrosis (grade 5 of pathological damage) was seen in the small intestinal mucosa of rats treated with FK506 + L-NAME. L-arginine treatment in part prevented diarrhoea, mortality and pathological damage of small intestinal mucosa induced by L-NAME. CONCLUSIONS: Inhibition of NOS induces intestinal mucosal damage and increases mortality in rats treated with FK506. L-arginine treatment can in part prevent the injury induced L-NAME. The present study suggests that NO, as an important protective factor, may be involved in the FK506-induced intestinal damage.     

NO在外源性高浓度Ca2+损伤心肌线粒体中的作用

目的：探讨一氧化氮在外源性高浓度Ca²⁺损伤心肌线粒体中的作用。方法：正常心肌线粒体分为单纯L-精氨酸（L-Arg）组、Ca²⁺损伤组和左旋硝基精氨酸甲酯（L-NAME）保护组,分别于含有20 μmol/L EDTA、100 μmol/L CaCl₂以及1 μmol/L L-NAME+100 μmol/L CaCl₂的反应介质中孵育,然后测定线粒体活力、膜电位以及NO含量。结果：Ca²⁺损伤组线粒体活力、膜电位明显下降,而NO^-₂/NO^-₃含量升高,且线粒体活力、膜电位与NO₂^-/NO₃^-含量呈显著负相关（r=-0.5297,P<0.01;r=-0.6041,P<0.01）;L-NAME保护组线粒体活力与膜电位均明显高于Ca²⁺损伤组,但仍低于L-Arg组,而NO₂^-/NO₃^-含量低于Ca²⁺损伤组,且与L-Arg组无明显差异。结论：外源性Ca²⁺可激活线粒体一氧化氮合酶,使NO生成增多,后者在线粒体活力与膜电位降低中起重要作用。     

Endogenous NO does not regulate baseline pulmonary pressure,but reduces acute pulmonary hypertension in dogs

It has remained unclear whether endogenous production of nitric oxide (NO) plays an important role in the regulation of physiologically normal pulmonary pressures. Severe alveolar hypoxia is accompanied by decreased pulmonary NO production, which could contribute to the development of hypoxic pulmonary hypertension. On the other hand, pharmacological NO inhibition further augments this hypertensive response. AIMS: The aims of the present study were to test: (a) whether NO contributes importantly in the maintenance of baseline pulmonary pressure; and (b) to which degree NO is involved in the pulmonary haemodynamic adjustments to alveolar hypoxia. METHODS: In anaesthetized dogs (n=37), the systemic and pulmonary haemodynamic effects of the NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME, 20 mg kg(-1)) and substrate, L-arginine (200-500 mg kg(-1)), were determined at baseline and during alveolar hypoxia. Constant blood flows were accomplished by biventricular bypass, and systemic normoxaemia was maintained by extracorporeal oxygenation. RESULTS: The primary findings were: (a) L-NAME failed to increase baseline mean pulmonary arterial pressure (10.1 +/- 0.7 vs. 10.5 +/- 0.5 mmHg, P=ns), despite effective NO synthase inhibition as evidenced by robust increases in systemic arterial pressures; (b) L-NAME augmented the pulmonary hypertensive response to alveolar hypoxia (10.2 +/- 0.7 to 19.5 +/- 1.7 with L-NAME vs. 9.9 +/- 1.1 to 15.5 +/- 1.0 mmHg without L-NAME, P<0.05); and (c) L-arginine failed to decrease baseline or elevated pulmonary pressures. Instead, prolonged L-arginine caused increases in pulmonary pressure. CONCLUSION: These findings suggest that NO plays no significant role in the tonic physiological control of pulmonary pressure, but endogenous NO becomes an important vasodilatory modulator during elevated pulmonary pressure.     

Dietary L-arginine level alters plasma nitric oxide and apha-1 acid glycoprotein concentrations, and splenocyte proliferation in male broiler chickens following Escherichia coli lipopolysaccharide injection

Experiments were conducted to determine the effect of dietary arginine (Arg) on nitric oxide (NO) production following injection with Escherichia coli lipopolysaccharide (LPS) and splenocyte proliferative response to concanavalin A in broilers. Birds were fed experimental diets containing Arg at levels of 6.5, 14.4 or 24.4 g/kg diet in experiment 1, and 6.5, 14.4 or 19.3 g/kg diet in experiment 2, respectively, for 7 days and were then intraperitoneally injected with LPS (2 mg/kg body weight) after 16 h fasting. Maximum NO production estimated by plasma nitrite concentration was observed 6 or 10 h after LPS injection in all Arg groups. Dietary Arg level and/or intake were positively associated with NO production. NO production at 6 or 10 h after LPS injection coincided with changes in plasma alpha-1 acid glycoprotein concentration, an acute phase substance, at 10 or 24 h post-LPS injection. Splenocyte proliferation in chicks fed on Arg-sufficient (14.4 g/kg) diet was greater that that in chicks fed Arg-deficient or -excess diets. The results suggest that dietary Arg level and/or intake proportionally affect NO production, and acute phase inflammatory responses following LPS injection, and that marginal deficiency or excess of dietary Arg might reduce splenocyte proliferative responses.     

Effects of nitric oxide inhibition on the spread of biotinylated dextran and on extracellular space parameters in the neostriatum of the male rat.

Volume transmission in the brain is mediated by the diffusion of neurotransmitters, modulators and other neuroactive substances in the extracellular space. The effects of nitric oxide synthase inhibition on extracellular space diffusion properties were studied using two different approaches, the histological dextran method and the real-time iontophoretic tetramethylammonium method. The spread of biotinylated dextran (mol. wt 3000) in the extracellular space was measured morphometrically following microinjection into the neostriatum of male rats. Two parameters were used to describe the spread of biotinylated dextran in brain tissue, namely, total volume of spread and the mean grey value. The nonspecific nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester (10-100 mg/kg) and NG-monomethyl-L-arginine acetate (30-200 mg/kg) decreased the total volume of spread of dextran in a dose-dependent manner. 7-Nitroindazole monosodium salt (50-100 mg/kg), a specific neuronal nitric oxide synthase inhibitor, did not change the total volume of spread of dextran. Using the tetramethylammonium method, the extracellular space diffusion properties can be described by the volume fraction (alpha = extracellular space volume/total tissue volume), tortuosity lambda (lambda2 = free diffusion coefficient/apparent diffusion coefficient in tissue), and non-specific uptake kappa' [Nicholson C. and Syková E. (1998) Trends Neurosci. 21, 207-215]. Nitric oxide synthase inhibition by NG-nitro-L-arginine methyl ester (50 mg/kg) had relatively little effect on volume fraction and tortuosity, and no changes were observed after NG-monomethyl-L-arginine acetate (20 mg/kg) or 7-nitroindazole monosodium salt (100 mg/kg) treatment. A substantial increase was found only in non-specific uptake, by 13% after NG-nitro-L-arginine methyl ester and by 16% after NG-monomethyl-L-arginine acetate, which correlates with the decreased total volume of spread of dextran observed with the dextran method. NG-Nitro-L-arginine methyl ester treatment (100 mg/kg) decreased striatal blood flow and increased mean arterial blood pressure. The changes in dextran spread and non-specific uptake can be explained by an increased capillary clearance following the inhibition of endothelial nitric oxide synthase, as neuronal nitric oxide synthase inhibition had no effect. The observed changes after non-specific nitric oxide synthase inhibition may affect the extracellular space concentration of neurotransmitters and modulators, and influence volume transmission pathways in the central nervous system by increased capillary and/or cellular clearance rather than by changes in extracellular space diffusion.     

Endogenous NO does not regulate baseline pulmonary pressure,but reduces acute pulmonary hypertension in dogs

It has remained unclear whether endogenous production of nitric oxide (NO) plays an important role in the regulation of physiologically normal pulmonary pressures. Severe alveolar hypoxia is accompanied by decreased pulmonary NO production, which could contribute to the development of hypoxic pulmonary hypertension. On the other hand, pharmacological NO inhibition further augments this hypertensive response. Aims: The aims of the present study were to test: (a) whether NO contributes importantly in the maintenance of baseline pulmonary pressure; and (b) to which degree NO is involved in the pulmonary haemodynamic adjustments to alveolar hypoxia. Methods: In anaesthetized dogs (n = 37), the systemic and pulmonary haemodynamic effects of the NO synthase inhibitor, N^ω‐nitro‐l ‐arginine methyl ester (l ‐NAME, 20 mg kg^?1) and substrate, l ‐arginine (200–500 mg kg^?1), were determined at baseline and during alveolar hypoxia. Constant blood flows were accomplished by biventricular bypass, and systemic normoxaemia was maintained by extracorporeal oxygenation. Results: The primary findings were: (a) l ‐NAME failed to increase baseline mean pulmonary arterial pressure (10.1 ± 0.7 vs. 10.5 ± 0.5 mmHg, P = ns), despite effective NO synthase inhibition as evidenced by robust increases in systemic arterial pressures; (b) l ‐NAME augmented the pulmonary hypertensive response to alveolar hypoxia (10.2 ± 0.7 to 19.5 ± 1.7 with l ‐NAME vs. 9.9 ± 1.1 to 15.5 ± 1.0 mmHg without l ‐NAME, P < 0.05); and (c) l ‐arginine failed to decrease baseline or elevated pulmonary pressures. Instead, prolonged l ‐arginine caused increases in pulmonary pressure. Conclusion: These findings suggest that NO plays no significant role in the tonic physiological control of pulmonary pressure, but endogenous NO becomes an important vasodilatory modulator during elevated pulmonary pressure.