Positive inotropic and lusitropic effects of HNO/NO- in failing hearts:: Independence from β-adrenergic signaling
Positive inotropic and lusitropic effects of HNO/NO- in failing hearts:: Independence from β-adrenergic signaling
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DOI：
10.1073/pnas.0937302100
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发表时间：
2003-04-29
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;Katori, T;Kass, DA
一氧化氮（NO）的单电子还原形式--在这里，我们测试了HNO/NO-是否增强衰竭心脏的收缩和舒张功能，以及与NO/硝酸盐相反，这种调节是否增强而不是减弱β-肾上腺素能刺激，并伴有血浆降钙素基因相关肽（CGRP）增加。输注由Angelis盐（AS）产生的HNO/NO-（10 μ g/kg/min，im.）对慢性心动过速起搏引起心力衰竭的清醒犬。AS几乎使收缩力加倍，增强舒张，降低心脏前负荷和后负荷（均P < 0.001），而不改变血浆cGMP。这与NO供体二乙胺（DEA）/NO或硝酸甘油（NTG）诱导的适度收缩抑制形成对比。尽管在前者中β-肾上腺素能和钙信号传导受到抑制，但在衰竭心脏中AS的促肾上腺素变化与对照组相似。AS的正性肌力作用与多巴酚丁胺相加，而DEA/NO减弱β-刺激，NTG是中性的。给予非衰竭心脏普萘洛尔完全阻断异丙肾上腺素刺激，但对AS变力性和增强lusitropy的影响极小。动脉血浆CGRP上升3倍与AS，但不改变DEA/NO或NTG，支持提出的作用，这种肽HNO/NO-心脏的行动。因此，HNO/NO-具有正性肌力作用和负性肌力作用，与NO/硝酸盐不同，其独立于β-肾上腺素能刺激并刺激CGRIP释放。这表明HNO/NO-供体用于治疗心力衰竭的潜力。
Nitroxyl anion (HNO/NO-), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO/NO- augments systolic and diastolic function of failing hearts, and whether contrary to NO/nitrates such modulation enhances rather than blunts beta-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO/NO- generated by Angelis' salt (AS) was infused (10 mug/kg per min, im.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P < 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine(DEA)/NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed beta-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA/NO blunted beta-stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA/NO or NTG, supporting a proposed role of this peptide to HNO/NO- cardiotropic action. Thus, HNO/NO- has positive inotropic and lusitropic action, which unlike NO/nitrates is independent and additive to beta-adrenergic stimulation and stimulates CGRIP release. This suggests potential of HNO/NO- donors for the treatment of heart failure.