Saitoh S, Saito T, Ohwada T, Ohtake A, Onogi F, Aikawa K, Maehara K, Maruyama Y
First Department of Internal Medicine, Fukushima Medical College, Japan.
Cardiovasc Res. 1998 Jun;38(3):772-81. doi: 10.1016/s0008-6363(98)00053-4.
We examined the morphological changes induced by repeated endothelial denudation in coronary artery (CA), as well as functional changes in the endothelium-dependent and smooth muscle responses to various vasoactive agents during the process of intimal thickening.
We observed vascular responses in denuded and non-denuded portions of pig CA while being fed a normal diet (n = 11, N group) or 2% cholesterol diet (n = 25, C group) to intracoronary acetylcholine (ACh), 5-hydroxytryptamine (5-HT), substance P (SP), and isosorbide dinitrate (ISDN) with and without the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg i.v.) over a period of 8 weeks. Balloon endothelial denudation of the left anterior descending CA was carried out every 2 weeks.
In N group, maximum vasoconstriction was obtained with ACh 2 weeks after the first denudation [26 +/- 5% vs. 1 +/- 1% pre-denudation, p < 0.05]. L-NAME did not affect ACh-induced CA diameter changes. Thereafter, the response to ACh was attenuated by repeated denudation in N groups. However, the degree of 5-HT-induced CA narrowing at the denuded portion increased from 7 +/- 4% (0 week) to 88 +/- 8% (8 weeks) (p < 0.05). The changes resulted in severe myocardial ischaemia, and suggested that endothelium-dependent vasodilation was progressively attenuated while hyperreactivity of vascular smooth muscle simultaneously increased. Vasodilation induced by SP was attenuated somewhat, but ISDN-induced vasodilation was preserved. Although mild hypercholesterolaemia was induced in C group, the vascular responses to these vasoactive agents did not differ from those of N group.
Repeated CA endothelial injury and regeneration induce the change of morphology and vascular reactivity in the denuded portion regardless of atherogenic diet. This study strongly suggests that intimal thickening caused by repeated endothelial injury and regeneration induces specific vascular responses to vasoactive agents. Moreover, it is also suggested that during the progression of intimal thickening, increased vascular smooth muscle contraction and decreased endothelium-dependent dilation appear in a stimulus-dependent manner, often leading to severe coronary vasoconstriction accompanied with definitive ECG ST change.
我们研究了冠状动脉（CA）反复内皮剥脱所诱导的形态学变化，以及在内膜增厚过程中内皮依赖性和平滑肌对各种血管活性药物反应的功能变化。
我们观察了正常饮食（n = 11，N组）或2%胆固醇饮食（n = 25，C组）喂养的猪CA剥脱和未剥脱部分对冠状动脉内乙酰胆碱（ACh）、5-羟色胺（5-HT）、P物质（SP）和硝酸异山梨酯（ISDN）的血管反应，在有和没有一氧化氮合成抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME，10mg/kg静脉注射）的情况下，持续8周。每2周对左前降支CA进行球囊内皮剥脱。
在N组中，第一次剥脱后2周，ACh可引起最大血管收缩[剥脱前为1±1%，剥脱后为26±5%，p < 0.05]。L-NAME不影响ACh诱导的CA直径变化。此后，N组中反复剥脱使对ACh的反应减弱。然而，5-HT诱导的剥脱部分CA狭窄程度从7±4%（0周）增加到88±8%（8周）（p < 0.05）。这些变化导致严重心肌缺血，提示内皮依赖性血管舒张逐渐减弱，而血管平滑肌的高反应性同时增加。SP诱导的血管舒张有所减弱，但ISDN诱导的血管舒张得以保留。尽管C组诱导了轻度高胆固醇血症，但对这些血管活性药物的血管反应与N组无差异。
反复的CA内皮损伤和再生会导致剥脱部分的形态和血管反应性发生变化，而与致动脉粥样硬化饮食无关。本研究强烈提示，反复内皮损伤和再生引起的内膜增厚会诱导血管对血管活性药物产生特定反应。此外，还提示在内膜增厚过程中，血管平滑肌收缩增加和内皮依赖性舒张减少以刺激依赖的方式出现，常导致严重冠状动脉收缩并伴有明确的心电图ST段改变。
