Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease.
Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease.
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DOI：
10.1161/circulationaha.110.990317
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发表时间：
2011-05-24
期刊：
影响因子：
37.8
通讯作者：
Quyyumi AA
中科院分区：
文献类型：
--
作者：
Ozkor MA;Murrow JR;Rahman AM;Kavtaradze N;Lin J;Manatunga A;Quyyumi AA
我们评估了内皮衍生超极化因子（EDHFs）在健康和疾病中对静息和激动剂刺激的血管扩张剂张力的贡献。采用四乙基氯化铵（TEA）抑制K+Ca通道激活，氟康唑抑制细胞色素P450 2c9介导的环氧二碳三烯酸合成。我们假设1)EDHFs通过K+Ca通道激活和环氧二碳三烯酸释放促进静息血管张力，2)EDHFs补偿静息时一氧化氮生物利用度降低和内皮依赖性血管扩张剂。在103名健康受试者和71名有多种危险因素的非高血压受试者中，采用静脉闭塞体积描图法测定了ng -单甲基- l-精氨酸（L-NMMA）、TEA、氟康唑及其联合应用前后的静息前臂血流量（FBF）。研究了这些拮抗剂对静息FBF、缓激肽和乙酰胆碱介导的血管舒张的影响。所有受试者的静息FBF随TEA和L-NMMA而降低（P<0.001），然而，与有危险因素的受试者相比，健康受试者对L-NMMA的血管收缩反应更大（P =0.04），对TEA的血管收缩反应更低（P =0.04）。氟康唑降低了所有受试者的静息FBF，添加TEA进一步降低了氟康唑后的FBF，提示细胞色素P450代谢物和其他超极化因子激活了K+Ca通道。在健康和高胆固醇血症受试者中，L-NMMA和TEA均能减弱缓激肽介导的血管舒张（P<0.001）。相比之下，乙酰胆碱介导的血管舒张在健康受试者中保持不变，但在高胆固醇血症中显着减弱（P<0.04）。首先，EDHFs通过激活TEA抑制的K+Ca通道，与NO一起促进静息微血管扩张张力。与健康受试者相比，具有多种危险因素的患者K+Ca通道激活的贡献大于NO。其次，K+Ca通道的激活仅部分通过环氧二碳三烯酸释放，表明存在其他超极化机制。第三，在健康受试者中，缓激肽而不是乙酰胆碱刺激K+Ca通道介导的血管舒张，而在高胆固醇血症中，K+Ca通道介导的血管舒张补偿了一氧化氮活性的降低。因此，在NO缺乏的情况下，EDHF活性的增强有助于维持静息和激动剂刺激的血管舒张。临床试验注册信息：http://clinicaltrials.gov/，标识符：NCT00166166
We assessed the contribution of endothelium-derived hyperpolarizing factors (EDHFs) to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was employed to inhibit K+Ca channel activation and fluconazole to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that 1) EDHFs contribute to resting vascular tone by K+Ca channel activation and epoxyeicosatrienoic acid release, and 2) EDHFs compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. In 103 healthy subjects and 71 non-hypertensive subjects with multiple risk factors, resting forearm blood flow (FBF) was measured using venous occlusion plethysmography before and after intra-arterial infusions of NG-monomethyl-L-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF, and on bradykinin- and acetylcholine-mediated vasodilation was studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001), however, the vasoconstrictor response to L-NMMA was greater (p=0.04) and to TEA lower (p=0.04) in healthy subjects compared to those with risk factors. Fluconazole decreased resting FBF in all subjects and addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate K+Ca channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects, but was significantly attenuated in hypercholesterolemia (P<0.04). Firstly, EDHFs by activating TEA inhibitable K+Ca channels together with NO contribute to resting microvascular dilator tone. The contribution of K+Ca channel activation compared to NO is greater in those with multiple risk factors compared to healthy subjects. Second, activation of K+Ca channels is only partly through epoxyeicosatrienoic acid release, indicating presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine stimulates K+Ca channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, K+Ca channel-mediated vasodilation compensates for the reduced NO activity. Thus, enhanced EDHF activity in conditions of NO deficiency contributes to maintenance of resting and agonist-stimulated vasodilation. Clinical Trial Registration Information: http://clinicaltrials.gov/, Identifier: NCT00166166