Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure
Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure
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DOI：
10.1161/01.cir.0000066283.13253.78
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发表时间：
2003-04-08
期刊：
影响因子：
37.8
通讯作者：
McVeigh, GE
中科院分区：
文献类型：
--
作者：
Dixon, LJ;Morgan, DR;McVeigh, GE
背景-充血性心力衰竭(CCF)患者内皮介导的血管扩张(EMVD)与一氧化氮(NO)生物利用度降低有关，因为它与主要来源于NAD(P)H依赖的氧化酶的血管超氧化物歧化(O-2(.-))相互作用。去偶联的内皮型一氧化氮合酶(ENOS)可产生O-2(.-)。我们研究了内皮型一氧化氮合酶去偶联对CCF患者血管内皮细胞变性的功能影响。方法和结果：我们用血小板作为一个分室的体外模型来检测O-2(.-)和NO的产生。当eNOS功能正常时，掺入N-omega-硝基-L-精氨酸甲酯(L-NAME，1 mmoL/L)可增加O-2(.-)的检测，因为抑制NO的产生阻止了NO对O-2(.-)的清除。这在对照组和9名CCF患者中观察到，在这些患者中，O-2(.-)检测分别增加了63%和101%。在其余9例CCF患者中，加入L-NAME使O-2(.-)的产生减少了39%，表明O-2(.-)的产生是通过eNOS解偶联产生的。内皮型一氧化氮合酶偶联组的血小板源性NO水平显著高于未偶联组(2.8+/-1.4和0.9+/-0.4pmol/10(8)血小板，P=0.04)。静脉阻塞体积描记术记录的内皮依赖性和非依赖性血管扩张反应在eNOS解偶联的患者中显著受损。结论：本研究首次提供了人CCF中血小板eNOS解偶联的证据。与酶解偶联相关，内皮依赖性和非依赖性血管扩张剂反应受损，血小板衍生NO产生减少。
Background-Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O-2(.-)), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase ( eNOS) produces O-2(.-). We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF.Methods and Results-We employed the platelet as a compartmentalized ex-vivo model to examine O-2(.-) and NO production. When eNOS is functioning normally, incorporation of N-omega-Nitro-L-Arginine methyl ester (L-NAME, 1 mmol/L), results in increased O-2(.-) detection, as inhibition of NO production prevents NO scavenging of O-2(.-). This was observed in controls and 9 of the CCF patients, in whom O-2(.-) detection increased by 63% and 101%, respectively. In the remaining 9 CCF patients, incorporation of L-NAME reduced O-2(.-) production by 39%, indicating O-2(.-) production by eNOS uncoupling. Detection of platelet-derived NO was significantly greater in eNOS-coupled platelets compared with the uncoupled group (2.8+/-1.4 versus 0.9+/-0.4 pmol/10(8) platelets, P=0.04). Endothelium-dependent and-independent vasodilator responses to acetylcholine and sodium nitroprusside recorded using venous occlusion plethysmography were significantly impaired in patients exhibiting eNOS uncoupling.Conclusions-This study provides first evidence that platelet eNOS can become uncoupled in human CCF. Impaired endothelium-dependent and -independent vasodilator responses and diminished platelet-derived NO production occurred in association with enzyme uncoupling.