Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Nutr Metab Cardiovasc Dis. 2011 Oct;21(10):808-16. doi: 10.1016/j.numecd.2010.02.006. Epub 2010 May 31.
given that obesity is an independent risk factor for the development of cardiovascular diseases we decided to investigate the mechanisms involved in microvascular dysfunction using a monosodium glutamate (MSG)-induced model of obesity, which allows us to work on both normotensive and normoglycemic conditions.
Male offspring of Wistar rats received MSG from the second to the sixth day after birth. Sixteen-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia and insulin resistance, with no alteration in glycemia and blood pressure. The effect of norepinephrine (NE), which was increased in MSG rats, was potentiated by L-nitro arginine methyl ester (L-NAME) or tetraethylammonium (TEA) and was reversed by indomethacin and NS-398. Sensitivity to acetylcholine (ACh), which was reduced in MSG rats, was further impaired by L-NAME or TEA, and was corrected by indomethacin, NS-398 and tetrahydrobiopterin (BH4). MSG rats displayed increased endothelium-independent relaxation to sodium nitroprusside. A reduced prostacyclin/tromboxane ratio was found in the mesenteric beds of MSG rats. Mesenteric arterioles of MSG rats also displayed reduced nitric oxide (NO) production along with increased reactive oxygen species (ROS) generation; these were corrected by BH4 and either L-NAME or superoxide dismutase, respectively. The protein expression of eNOS and cyclooxygenase (COX)-2 was increased in mesenteric arterioles from MSG rats.
Obesity/insulin resistance has a detrimental impact on vascular function. Reduced NO bioavailability and increased ROS generation from uncoupled eNOS and imbalanced release of COX products from COX-2 play a critical role in the development of these vascular alterations.
鉴于肥胖是心血管疾病发展的独立危险因素，我们决定使用谷氨酸单钠（MSG）诱导的肥胖模型来研究微血管功能障碍的相关机制，该模型可用于研究正常血压和血糖条件下的情况。
Wistar 大鼠的雄性后代在出生后的第二至第六天接受 MSG。16 周龄的 MSG 大鼠表现出更高的 Lee 指数、脂肪堆积、血脂异常和胰岛素抵抗，血糖和血压没有变化。在 MSG 大鼠中，去甲肾上腺素（NE）的作用增强，这种增强作用可被 L-硝基精氨酸甲酯（L-NAME）或四乙铵（TEA）增强，并可被吲哚美辛和 NS-398 逆转。对乙酰胆碱（ACh）的敏感性降低，在 MSG 大鼠中进一步受损，可被 L-NAME 或 TEA 进一步损害，并可被吲哚美辛、NS-398 和四氢生物蝶呤（BH4）纠正。MSG 大鼠对硝普钠的非内皮依赖性舒张作用增强。在 MSG 大鼠的肠系膜床中发现前列腺素/血栓素比值降低。MSG 大鼠的肠系膜小动脉也显示一氧化氮（NO）生成减少，同时活性氧（ROS）生成增加；这些分别通过 BH4 和 L-NAME 或超氧化物歧化酶得到纠正。MSG 大鼠肠系膜小动脉中 eNOS 和环氧化酶（COX）-2 的蛋白表达增加。
肥胖/胰岛素抵抗对血管功能有不利影响。从脱偶联的 eNOS 产生的减少的 NO 生物利用度和增加的 ROS 生成以及 COX-2 不平衡释放的 COX 产物在这些血管改变的发展中起关键作用。
