Pfister S L, Campbell W B
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
Hypertension. 1996 Mar;27(3 Pt 2):804-10. doi: 10.1161/01.hyp.27.3.804.
Alterations in vascular tone are well documented in hypercholesterolemia, yet little is known about the role of dietary cholesterol in endothelium-dependent contractions of pulmonary arteries. Methacholine and arachidonic acid cause endothelium-dependent contractions in normal rabbit pulmonary artery that are mediated by thromboxane A2. We tested the effect of these agonists on pulmonary arteries from rabbits fed standard rabbit chow or chow supplemented with 2% cholesterol for 2 weeks. Arachidonic acid-induced contractions did not differ in the groups. However, methacholine-induced contractions were significantly depressed in cholesterol-fed rabbits. Vascular thromboxane A2 production was similar in normal and cholesterol-fed rabbits. Pretreatment with the nitric oxide synthase inhibitor nitro-L-arginine had no effect on contractions observed with methacholine in normal rabbits but enhanced methacholine-induced contractions in cholesterol-fed rabbits. In norepinephrine-precontracted vessels, methacholine caused a small relaxation response in normal rabbits. In contrast, in cholesterol-fed rabbits, methacholine produced enhanced relaxations, suggesting that cholesterol feeding augments relaxations and decreases contractions by increasing nitric oxide. However, nitric oxide synthase activity in pulmonary arteries from cholesterol-fed and normal rabbits was not different between the two groups. In an additional experiment, the calcium-dependent potassium channel blocker charybdotoxin had little effect on methacholine-induced contractions in cholesterol-fed rabbits. In summary, the present study demonstrates that hypercholesterolemia alters pulmonary artery vascular contractions and relaxations to methacholine. This effect is not mediated by a decreased production of thromboxane A2 or by an increased production of nitric oxide. Although the mechanisms mediating the altered vascular responses is still unknown, the results from this study clearly indicate that the regulation of vascular tone is different in normal and hypercholesterolemic vessels.
高胆固醇血症时血管张力的改变已有充分记录，但饮食胆固醇在肺动脉内皮依赖性收缩中的作用却知之甚少。乙酰甲胆碱和花生四烯酸可引起正常兔肺动脉的内皮依赖性收缩，这是由血栓素A2介导的。我们测试了这些激动剂对喂食标准兔饲料或添加2%胆固醇的饲料2周的兔肺动脉的影响。花生四烯酸诱导的收缩在两组中没有差异。然而，乙酰甲胆碱诱导的收缩在喂食胆固醇的兔中明显受到抑制。正常兔和喂食胆固醇的兔的血管血栓素A2生成相似。用一氧化氮合酶抑制剂硝基-L-精氨酸预处理对正常兔乙酰甲胆碱引起的收缩没有影响，但增强了喂食胆固醇的兔中乙酰甲胆碱诱导的收缩。在去甲肾上腺素预收缩的血管中，乙酰甲胆碱在正常兔中引起小的舒张反应。相反，在喂食胆固醇的兔中，乙酰甲胆碱产生增强的舒张，表明喂食胆固醇通过增加一氧化氮来增强舒张并减少收缩。然而，喂食胆固醇的兔和正常兔肺动脉中的一氧化氮合酶活性在两组之间没有差异。在另一项实验中，钙依赖性钾通道阻滞剂蝎毒素对喂食胆固醇的兔中乙酰甲胆碱诱导的收缩影响很小。总之，本研究表明高胆固醇血症改变了肺动脉对乙酰甲胆碱的血管收缩和舒张。这种作用不是由血栓素A2生成减少或一氧化氮生成增加介导的。尽管介导血管反应改变的机制仍然未知，但本研究结果清楚地表明正常血管和高胆固醇血症血管中血管张力的调节是不同的。
