Effects of chronic heart failure on neuronal nitric oxide synthase-mediated control of microvascular O2 pressure in contracting rat skeletal muscle.
Effects of chronic heart failure on neuronal nitric oxide synthase-mediated control of microvascular O2 pressure in contracting rat skeletal muscle.
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慢性心力衰竭对神经元一氧化氮合酶介导的大鼠骨骼肌收缩微血管 O2 压力控制的影响。
DOI：
10.1113/jphysiol.2012.235929
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Poole,DavidC
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作者：
Copp,StevenW;Hirai,DanielM;Ferguson,ScottK;Holdsworth,ClarkT;Musch,TimothyI;Poole,DavidC
关键点·一氧化氮（NO）是一种重要的血管舒张信号分子，可调节骨骼肌微血管内的O2压力（）。在健康受试者中，NO来源于两种主要的NO合酶（NOS）亚型：神经元NOS（nNOS）和内皮NOS（eNOS）。·慢性心力衰竭（CHF）导致外周血管功能障碍，部分原因是NO功能受损。这种NO介导的损伤通常归因于eNOS功能障碍。尚不清楚nNOS介导的功能调节在CHF中是否受损。我们目前的研究结果表明，在健康大鼠中观察到的nNOS抑制后骨骼肌血流减少和收缩期间的变化在CHF大鼠中明显减弱或不存在，这表明nNOS功能受损。识别CHF微血管功能受损的潜在机制是开发旨在改善CHF诱导的骨骼肌微血管病理学的治疗方法的重要一步。AbstractChronic heart failure（CHF）improves nitric oxide（NO）-mediated regulation of the skeletal muscle microvascular O2 delivery/ ratio（which sets the microvascular O2 pressure，）.鉴于CHF中内皮功能障碍的普遍性，这种NO介导的失调通常归因于eNOS。尚不清楚nNOS介导的调节在CHF中是否改变。我们检验了CHF损害nNOS介导的控制的假设。在健康和CHF（左心室舒张末期压（LVEDP）：分别为6 ± 1和14 ± 1 mmHg，P< 0.05）大鼠中，在0.56 mg kg− 1选择性nNOS受体或S-甲基-l-硫代瓜氨酸（SMTC）静脉注射之前和之后，测量脊髓背角肌血流量（放射性标记微球）、（磷光猝灭）和（Fick计算）。在健康大鼠中，SMTC通过降低（↓20%）而增加基线（对照：29.7 ± 1.4，SMTC：34.4 ± 1.9 mmHg，P< 0.05），对血流无任何影响，并加快平均反应时间（MRT，达到总动力学反应63%的时间，对照：24.2 ± 2.0，SMTC：18.5 ± 1.3 s，P< 0.05）。在CHF大鼠中，SMTC没有改变基线（对照：25.7 ± 1.6，SMTC：28.6 ± 2.1 mmHg，P> 0.05），在休息时，或MRT（对照：22.8 ± 2.6，SMTC：21.3 ± 3.0 s，P> 0.05）。在收缩稳态期间，SMTC减少健康大鼠的血流量（↓15%）和（↓15%），但未发生改变（对照组：19.8 ± 1.7，SMTC：20.7 ± 1.8 mmHg，P> 0.05）。与此形成鲜明对比的是，在CHF大鼠中，SMTC不改变收缩稳态血流量，或（对照：17.0 ± 1.4，SMTC：17.7 ± 1.8 mmHg，P> 0.05）。nNOS介导的骨骼肌微血管功能控制在CHF与健康大鼠中受损。旨在改善CHF微血管功能障碍的治疗可能通过靶向改善nNOS功能而获益。
Key points•Nitric oxide (NO) is an important vasodilatory signalling molecule that regulates O2pressure within the skeletal muscle microvasculature (). In healthy subjects, NO is derived from two principal NO synthase (NOS) isoforms: neuronal NOS (nNOS) and endothelial NOS (eNOS).•Chronic heart failure (CHF) results in peripheral vascular dysfunction that is attributed, in part, to impaired NO function. This NO‐mediated impairment is attributed generally to eNOS dysfunction. It is unknown if nNOS‐mediated regulation of function is impaired in CHF.•Our present results demonstrate that skeletal muscle blood flow reductions and alterations during contractions observed following nNOS inhibition in healthy rats are markedly attenuated or absent in CHF rats, which is indicative of impaired nNOS function.•Identification of the mechanisms underlying impaired microvascular function in CHF is an important step in the development of treatments designed to improve CHF‐induced skeletal muscle microvascular pathology.AbstractChronic heart failure (CHF) impairs nitric oxide (NO)‐mediated regulation of the skeletal muscle microvascular O2delivery/ ratio (which sets the microvascular O2pressure, ). Given the pervasiveness of endothelial dysfunction in CHF, this NO‐mediated dysregulation is attributed generally to eNOS. It is unknown whether nNOS‐mediated regulation is altered in CHF. We tested the hypothesis that CHF impairs nNOS‐mediated control. In healthy and CHF (left ventricular end diastolic pressure (LVEDP): 6 ± 1versus14 ± 1 mmHg, respectively,P< 0.05) rats spinotrapezius muscle blood flow (radiolabelled microspheres), (phosphorescence quenching), and (Fick calculation) were measured before and after 0.56 mg kg−1i.a.of the selective nNOS inhibitorS‐methyl‐l‐thiocitrulline (SMTC). In healthy rats, SMTC increased baseline (Control: 29.7 ± 1.4, SMTC: 34.4 ± 1.9 mmHg,P< 0.05) by reducing (↓20%) without any effect on blood flow and speeded the mean response time (MRT, time to reach 63% of the overall kinetics response, Control: 24.2 ± 2.0, SMTC: 18.5 ± 1.3 s,P< 0.05). In CHF rats, SMTC did not alter baseline (Control: 25.7 ± 1.6, SMTC: 28.6 ± 2.1 mmHg,P> 0.05), at rest, or the MRT (Control: 22.8 ± 2.6, SMTC: 21.3 ± 3.0 s,P> 0.05). During the contracting steady‐state, SMTC reduced blood flow (↓15%) and (↓15%) in healthy rats such that was unaltered (Control: 19.8 ± 1.7, SMTC: 20.7 ± 1.8 mmHg,P> 0.05). In marked contrast, in CHF rats SMTC did not change contracting steady‐state blood flow, , or (Control: 17.0 ± 1.4, SMTC: 17.7 ± 1.8 mmHg,P> 0.05). nNOS‐mediated control of skeletal muscle microvascular function is compromised in CHFversushealthy rats. Treatments designed to ameliorate microvascular dysfunction in CHF may benefit by targeting improvements in nNOS function.