Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.
Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.
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DOI：
10.1016/j.yjmcc.2011.05.017
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发表时间：
2011-10
影响因子：
5
通讯作者：
Kass DA
中科院分区：
文献类型：
--
作者：
Moens AL;Ketner EA;Takimoto E;Schmidt TS;O'Neill CA;Wolin MS;Alp NJ;Channon KM;Kass DA
外源性给予四氢生物蝶呤（BH 4），一氧化氮合酶（NOS）的一种必需的辅因子，已被证明可以减少左心室肥大，纤维化和心脏功能障碍的小鼠与预先建立的心脏病引起的压力超负荷。在这种情况下，BH 4重新偶联内皮NOS（eNOS），随后减少NOS依赖性氧化应激和逆转适应不良的重塑。然而，最近的研究表明，有效的BH 4剂量可能比以前认为的要窄，这可能是由于口服时的氧化作用。因此，我们评估了每日口服合成的沙丙蝶呤二盐酸盐（6-R-L-双氯-5，6，7，8-四氢生物蝶呤，6 R-BH 4）对预先建立的压力超负荷心脏病的剂量反应。小鼠（n=64）通过口服小的预制颗粒（在15-30分钟内消耗）给予0-400 mg/kg/d BH 4。在36-200 mg/kg/d的剂量范围内，6 R-BH 4抑制了心腔重塑、肥大、纤维化和压力超负荷的氧化应激。然而，在较低和较高剂量下，BH 4具有较少或没有改善作用。有效剂量与较高的心肌BH 4/BH 2比值相关。然而，BH 2随剂量线性升高，在400 mg/kg/d剂量下，BH 4/BH 2比值降低至对照组水平。这些结果暴露了BH 4临床应用的潜在局限性，因为细胞氧化还原的可变性和心脏病可能会在个体之间产生可变的治疗窗口。
The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-coupled endothelial NOS (eNOS), with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling. However, recent studies suggest the effective BH4 dosing may be narrower than previously thought, potentially due to its oxidation upon oral consumption. Accordingly, we assessed the dose response of daily oral synthetic sapropterin dihydrochloride (6-R-L-erythro-5,6,7,8-tetrahydrobiopterin, 6R-BH4) on pre-established pressure-overload cardiac disease. Mice (n=64) were administered 0-400 mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200 mg/kg/d, 6R-BH4 suppressed cardiac chamber remodeling, hypertrophy, fibrosis, and oxidative stress with pressure-overload. However, at both lower and higher doses, BH4 had less or no ameliorative effects. The effective doses correlated with a higher myocardial BH4/BH2 ratio. However, BH2 rose linearly with dose, and at the 400 mg/kg/d, this lowered the BH4/BH2 ratio back towards control. These results expose a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals.
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DOI：
10.1152/ajpheart.00823.2007
发表时间：
2008-04-01
影响因子：
4.8
作者：
Crabtree, Mark J.;Smith, Caroline L.;Gross, Steven S.
通讯作者：
Gross, Steven S.
影响因子：
2.7
作者：
Porkert, M.;Sher, S.;Quyyumi, A. A.
通讯作者：
Quyyumi, A. A.
影响因子：
168.9
作者：
Levy, Harvey L.;Milanowski, Andrzej;Dorenbaum, Alex
通讯作者：
Dorenbaum, Alex
影响因子：
3.8
作者：
Fiege, B;Ballhausen, D;Blau, N
通讯作者：
Blau, N
影响因子：
5.3
作者：
Settergren, M.;Bohm, F.;Pernow, J.
通讯作者：
Pernow, J.