Tada H, Thompson C I, Recchia F A, Loke K E, Ochoa M, Smith C J, Shesely E G, Kaley G, Hintze T H
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Circ Res. 2000 Feb 18;86(3):270-4. doi: 10.1161/01.res.86.3.270.
Although the role of nitric oxide (NO) in the modulation of vascular tone has been studied and well understood, its potential role in the control of myocardial metabolism is only recently evident. Several lines of evidence indicate that NO regulates myocardial glucose metabolism; however, the details and mechanisms responsible are still unknown. The aim of this study was to further define the role of NO in the control of myocardial glucose metabolism and the nitric oxide synthase (NOS) isoform responsible using transgenic animals lacking endothelial NOS (ecNOS). In the present study, we examined the regulation of myocardial glucose uptake using isometrically contracting Langendorff-perfused hearts from normal mice (C57BL/6J), mice with defects in the expression of ecNOS [ecNOS (-/-)], and its heterozygote [ecNOS (+/-)], and wild-type mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice, little myocardial glucose uptake was observed. This myocardial glucose uptake increased significantly in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME). Similarly, in the hearts from ecNOS (-/-), glucose uptake was much greater than in normal mice, whereas myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice was not different from normal mice. In addition, myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice increased significantly in the presence of L-NAME. At a workload of 800 g. beats/min, L-NAME increased glucose uptake from 0.1+/-0.1 to 3+/-0.4 microg/min x mg in ecNOS (+/-) mice and from 0.2+/-0.1 to 2.7+/-0.7 microg/min x mg in ecNOS (+/+) mice. Furthermore, in the hearts from ecNOS (-/-) mice, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog or S-nitroso-N-acetylpenicillamine (SNAP), a NO donor essentially shut off glucose uptake, and in hearts from ecNOS (+/-) mice, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), an inhibitor of cGMP, increased the glucose uptake significantly. These results indicate clearly that cardiac NO production regulates myocardial glucose uptake via a cGMP-dependent mechanism and strongly suggest that ecNOS plays a pivotal role in this regulation. These findings may be important in the understanding of the pathogenesis of the diseases such as ischemic heart disease, heart failure, diabetes mellitus, hypertension, and hypercholesterolemia, in which NO synthesis is altered and substrate utilization by the heart changes.
尽管一氧化氮（NO）在调节血管张力方面的作用已得到研究并被充分理解，但其在控制心肌代谢中的潜在作用直到最近才显现出来。多条证据表明，NO调节心肌葡萄糖代谢；然而，具体细节和相关机制仍不清楚。本研究的目的是利用缺乏内皮型一氧化氮合酶（ecNOS）的转基因动物，进一步明确NO在控制心肌葡萄糖代谢中的作用以及负责的一氧化氮合酶（NOS）同工型。在本研究中，我们使用来自正常小鼠（C57BL/6J）、ecNOS表达有缺陷的小鼠[ecNOS（-/-）]及其杂合子[ecNOS（+/-）]和野生型小鼠[ecNOS（+/+）]（每组n = 6）的等长收缩的Langendorff灌注心脏，研究了心肌葡萄糖摄取的调节情况。在正常小鼠的心脏中，观察到心肌葡萄糖摄取很少。在存在N（ω）-硝基-L-精氨酸甲酯（L-NAME）的情况下，这种心肌葡萄糖摄取显著增加。同样，在ecNOS（-/-）小鼠的心脏中，葡萄糖摄取比正常小鼠大得多，而ecNOS（+/-）和ecNOS（+/+）小鼠的心肌葡萄糖摄取与正常小鼠没有差异。此外，在存在L-NAME的情况下，ecNOS（+/-）和ecNOS（+/+）小鼠的心肌葡萄糖摄取显著增加。在800 g·次/分钟的工作负荷下，L-NAME使ecNOS（+/-）小鼠的葡萄糖摄取从0.1±0.1增加到3±0.4 μg/分钟·毫克，使ecNOS（+/+）小鼠的葡萄糖摄取从0.2±0.1增加到2.7±0.7 μg/分钟·毫克。此外，在ecNOS（-/-）小鼠的心脏中，cGMP类似物8-溴鸟苷3':5'-环一磷酸（8-Br-cGMP）或NO供体S-亚硝基-N-乙酰青霉胺（SNAP）基本上阻断了葡萄糖摄取，而在ecNOS（+/-）小鼠的心脏中，cGMP抑制剂1H-[1,2,4]恶二唑并[4,3,-a]喹喔啉-1-酮（ODQ）显著增加了葡萄糖摄取。这些结果清楚地表明，心脏NO的产生通过cGMP依赖性机制调节心肌葡萄糖摄取，并强烈表明ecNOS在这种调节中起关键作用。这些发现对于理解诸如缺血性心脏病、心力衰竭、糖尿病、高血压和高胆固醇血症等疾病的发病机制可能很重要，在这些疾病中，NO合成发生改变，心脏的底物利用也发生变化。
