Malmsjö M, Bergdahl A, Zhao X H, Sun X Y, Hedner T, Edvinsson L, Erlinge D
Department of Internal Medicine, Lund University Hospital, Sweden.
Cardiovasc Res. 1999 Jul;43(1):200-9. doi: 10.1016/s0008-6363(99)00062-0.
Congestive heart failure (CHF) is accompanied by impaired peripheral blood flow and endothelial dysfunction with decreased release of nitric oxide (NO). Strong evidence supports the existence of another vasodilatory substance, endothelium derived hyperpolarising factor (EDHF), which has not previously been studied in CHF.
CHF was induced by left coronary artery ligation resulting in a reproducible myocardial infarction in Sprague Dawley rats. Vasodilatory responses to acetylcholine and extracellular nucleotides (ATP, ADP beta S, ADP and UTP) were examined in cylindrical segments of the mesenteric artery, precontracted with noradrenaline. The combined NO- and EDHF-dilatation (after inhibition of cyclo-oxygenase pathways) was called "total dilatation", as indomethacin had only minor effects in this system. NO-dilatation was studied in segments pretreated with indomethacin and the potassium channel inhibitors charybdotoxin (10(-7.5) M) and apamin (10(-6) M), while EDHF-dilatations were studied in the presence of indomethacin (10(-5) M) and L-NOARG (10(-3.5) M).
EDHF-dilatations in CHF were strongly up-regulated for ACh (36% vs. 73%; sham vs. CHF operated rats), ADP beta S (10% vs. 42%), ADP (0% vs. 21%) and UTP (3% vs. 35%). These dilatations were abolished by a combination of charybdotoxin and apamin, confirming that they were mediated by EDHF. The NO-dilatations on the other hand were down-regulated in CHF as compared to sham operated rats for ACh (93% vs. 76%; sham vs. CHF operated rats), ADP beta S (61% vs. 37%). ADP (60% vs. 30%), ATP (49% vs. 34%) and UTP (65% vs. 47%), while a minor decrease was seen in the total dilatation for ACh (87% vs. 75%; sham vs. CHF operated rats), ADP beta S (47% vs. 42%), ADP (59% vs. 39%), ATP (52% vs. 39%) and UTP (59% vs. 44%).
In this model of non-atherosclerotic CHF there was a minor decrease in the total dilatation and a marked down-regulation of the NO-mediated dilatation, while the EDHF-dilatation was up-regulated. Increased EDHF-activity in CHF may represent a compensatory response to decreased NO-activity to preserve endothelial function and tissue perfusion.
充血性心力衰竭（CHF）伴有外周血流受损和内皮功能障碍，一氧化氮（NO）释放减少。有力证据支持另一种血管舒张物质——内皮衍生超极化因子（EDHF）的存在，此前尚未在CHF中对其进行研究。
通过结扎左冠状动脉诱导CHF，在Sprague Dawley大鼠中导致可重复的心肌梗死。在用去甲肾上腺素预收缩的肠系膜动脉圆柱段中，检测对乙酰胆碱和细胞外核苷酸（ATP、β,γ-亚甲基二磷酸腺苷（ADPβS）、ADP和UTP）的血管舒张反应。在抑制环氧化酶途径后，NO和EDHF联合介导的舒张（“总舒张”），因为吲哚美辛在该系统中作用较小。在用吲哚美辛以及钾通道抑制剂蝎毒素（10^(-7.5)M）和蜂毒明肽（10^(-6)M）预处理的节段中研究NO介导的舒张，而在存在吲哚美辛（10^(-5)M）和L-硝基精氨酸甲酯（L-NOARG，10^(-3.5)M）的情况下研究EDHF介导的舒张。
CHF中对乙酰胆碱（假手术组与CHF手术组大鼠：36%对73%）、ADPβS（10%对42%）、ADP（0%对21%）和UTP（3%对35%）的EDHF介导的舒张显著上调。这些舒张反应被蝎毒素和蜂毒明肽的联合使用所消除，证实它们是由EDHF介导的。另一方面，与假手术组大鼠相比，CHF中对乙酰胆碱（93%对76%）、ADPβS（61%对37%）、ADP（60%对30%）、ATP（49%对34%）和UTP（65%对47%）的NO介导的舒张下调，而对乙酰胆碱（87%对75%）、ADPβS（47%对42%）、ADP（59%对39%）、ATP（52%对39%）和UTP（59%对44%）的总舒张有轻微下降。
在这种非动脉粥样硬化性CHF模型中，总舒张有轻微下降，NO介导的舒张显著下调，而EDHF介导的舒张上调。CHF中EDHF活性增加可能代表对NO活性降低的一种代偿反应，以维持内皮功能和组织灌注。
