Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling
Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling
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DOI：
10.1073/pnas.181191198
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发表时间：
2001-08-28
影响因子：
11.1
通讯作者：
Kass, DA
中科院分区：
文献类型：
--
作者：
Paolocci, N;Saavedra, WF;Kass, DA
硝酰阴离子（NO-）是一氧化氮（NO.）的单电子还原产物，由NO合酶在体外酶促产生。 NO-在体内的生理活性和作用机制仍不清楚。将 NO 发生器 Angeli 盐（AS，Na2N2O3）给予有意识的长期仪器狗，并使用压力维度分析来区分收缩和外周血管反应。 AS 迅速增强左心室收缩力，同时降低心脏前负荷量和舒张压（静脉舒张），而动脉阻力没有变化。动脉或静脉血浆 cGMP 没有相关变化。尽管用六甲铵或容量再扩张进行反射阻断，正性肌力反应是相似的，表明其独立于压力反射刺激。然而，反射激活确实在基础条件下观察到的选择性静脉扩张中发挥了主要作用。这些数据与纯NO供体二乙胺/NO形成对比，后者引起可忽略不计的正性肌力反应和更平衡的静脉/动脉扩张。 AS 诱导的正性肌力，而非全身血管舒张，对氧化还原高度敏感，实际上可被 N-乙酰基-L-半胱氨酸的共混所抑制。 NO- 的心脏正性肌力信号传导是由降钙素基因相关肽 (CGRP) 介导的，因为用选择性 CGRP 受体拮抗剂 CGRP-(8-37) 治疗可以阻止这种作用，但不能阻止全身血管舒张。因此，NO-是一种氧化还原敏感的正性肌力药物，具有选择性静脉扩张作用，其心脏作用是由 CGRP 受体刺激介导的。这一事实是通过非肾上腺素能/非胆碱能肽信号传导将NO-与氧化还原敏感的心脏收缩调节联系起来的证据。鉴于其心脏和血管特性，NO-可能有助于治疗以心脏抑制和静脉充盈压升高为特征的心血管疾病。
Nitroxyl anion (NO-) is the one-electron reduction product of nitric oxide (NO.) and is enzymatically generated by NO synthase in vitro. The physiologic activity and mechanism of action of NO- in vivo remains unknown. The NO- generator Angeli's salt (AS, Na2N2O3) was administered to conscious chronically instrumented dogs, and pressure-dimension analysis was used to discriminate contractile from peripheral vascular responses. AS rapidly enhanced left ventricular contractility and concomitantly lowered cardiac preload volume and diastolic pressure (venodilation) without a change in arterial resistance. There were no associated changes in arterial or venous plasma cGMP. The inotropic response was similar despite reflex blockade with hexamethonium or volume reexpansion, indicating its independence from baroreflex stimulation. However, reflex activation did play a major role in the selective venodilation observed under basal conditions. These data contrasted with the pure NO donor diethylamine/NO, which induced a negligible inotropic response and a more balanced veno/arterial dilation. AS-induced positive inotropy, but not systemic vasodilatation, was highly redox-sensitive, being virtually inhibited by coinfusion of N-acetyl-L-cysteine. Cardiac inotropic signaling by NO- was mediated by calcitonin gene-related peptide (CGRP), as treatment with the selective CGRP-receptor antagonist CGRP-(8-37) prevented this effect but not systemic vasodilation. Thus, NO- is a redox-sensitive positive inotrope with selective venodilator action, whose cardiac effects are mediated by CGRP-receptor stimulation. This fact is evidence linking NO- to redox-sensitive cardiac contractile modulation by nonadrenergic/noncholinergic peptide signaling. Given its cardiac and vascular properties, NO- may prove useful for the treatment of cardiovascular diseases characterized by cardiac depression and elevated venous filling pressures.