d'Agostino Chiara, Labinskyy Volodymyr, Lionetti Vincenzo, Chandler Margaret P, Lei Biao, Matsuo Ken, Bellomo Michelle, Xu Xiaobin, Hintze Thomas H, Stanley William C, Recchia Fabio A
Dept. of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Am J Physiol Heart Circ Physiol. 2006 Apr;290(4):H1721-6. doi: 10.1152/ajpheart.00745.2005. Epub 2006 Jan 20.
Acute inhibition of nitric oxide (NO) synthase causes a reversible alteration in myocardial substrate metabolism. We tested the hypothesis that prolonged NO synthase inhibition alters cardiac metabolic phenotype. Seven chronically instrumented dogs were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 35 mg.kg(-1).day(-1) po) for 10 days to inhibit NO synthesis, and seven were used as controls. Cardiac free fatty acid, glucose, and lactate oxidation were measured by infusion of [(3)H]oleate, [(14)C]glucose, and [(13)C]lactate, respectively. After 10 days of L-NAME administration, despite no differences in left ventricular afterload, cardiac O(2) consumption was significantly increased by 30%, consistent with a marked enhancement in baseline oxidation of glucose (6.9 +/- 2.0 vs. 1.7 +/- 0.5 micromol.min(-1).100 g(-1), P < 0.05 vs. control) and lactate (21.6 +/- 5.6 vs. 11.8 +/- 2.6 micromol.min(-1).100 g(-1), P < 0.05 vs. control). When left ventricular afterload was increased by ANG II infusion to stimulate myocardial metabolism, glucose oxidation was augmented further in the L-NAME than in the control group, whereas free fatty acid oxidation decreased. Exogenous NO (diethylamine nonoate, 0.01 micromol.kg(-1).min(-1) iv) could not reverse this metabolic alteration. Consistent with the accelerated rate of carbohydrate oxidation, total myocardial pyruvate dehydrogenase activity and protein expression were higher (38 and 34%, respectively) in the L-NAME than in the control group. Also, protein expression of the constitutively active glucose transporter GLUT-1 was significantly elevated (46%) vs. control. We conclude that prolonged NO deficiency causes a profound alteration in cardiac metabolic phenotype, characterized by selective potentiation of carbohydrate oxidation, that cannot be reversed by a short-term infusion of exogenous NO. This phenomenon may constitute an adaptive mechanism to counterbalance cardiac mechanical inefficiency.
一氧化氮（NO）合酶的急性抑制会导致心肌底物代谢发生可逆性改变。我们检验了这样一个假设，即长期抑制NO合酶会改变心脏代谢表型。7只长期植入仪器的犬接受N（ω）-硝基-L-精氨酸甲酯（L-NAME，35 mg·kg⁻¹·天⁻¹，口服）治疗10天以抑制NO合成，另外7只作为对照。分别通过输注[³H]油酸、[¹⁴C]葡萄糖和[¹³C]乳酸来测量心脏游离脂肪酸、葡萄糖和乳酸的氧化。给予L-NAME 10天后，尽管左心室后负荷无差异，但心脏耗氧量显著增加30%，这与葡萄糖（6.9±2.0对1.7±0.5 μmol·min⁻¹·100 g⁻¹，与对照组相比P<0.05）和乳酸（21.6±5.6对11.8±2.6 μmol·min⁻¹·100 g⁻¹，与对照组相比P<0.05）的基础氧化显著增强一致。当通过输注血管紧张素II增加左心室后负荷以刺激心肌代谢时，L-NAME组的葡萄糖氧化比对照组进一步增加，而游离脂肪酸氧化减少。外源性NO（二乙胺硝普钠，0.01 μmol·kg⁻¹·min⁻¹，静脉注射）不能逆转这种代谢改变。与碳水化合物氧化速率加快一致，L-NAME组心肌丙酮酸脱氢酶的总活性和蛋白表达均高于对照组（分别为38%和34%）。此外，组成型活性葡萄糖转运体GLUT-1的蛋白表达与对照组相比显著升高（46%）。我们得出结论，长期NO缺乏会导致心脏代谢表型发生深刻改变，其特征为碳水化合物氧化的选择性增强，短期输注外源性NO无法逆转这种改变。这种现象可能构成一种适应性机制，以抵消心脏机械效率低下的问题。
