Vascular Physiology and Pharmacology Laboratory, Bioenginnering Department (INSIBIO-CONICET), Natural Sciences College, National University of Tucuman, Tucuman, Argentina.
J Cardiovasc Pharmacol. 2012 Jan;59(1):49-57. doi: 10.1097/FJC.0b013e318235156a.
This study was conducted to explore the vascular reactivity of angiotensin II and noradrenaline and their relationship with endothelial function in rabbits fed a high-fat diet (HFD). The animals were fed either an HFD or regular chow [control diet (CD)]. After 12 weeks, the rabbits fed the HFD showed higher blood pressure, body weight, and insulin levels. Glucose tolerance was impaired and positively related to blood pressure. An endothelium-independent decrease of the sensitivity to angiotensin II [pD2 endothelium-intact aortic rings (E+) in CD: 8.02 ± 0.07 vs. HFD: 7.60 ± 0.01; pD2 endothelium-removed aortic rings (E-) in CD: 8.16 ± 0.11 vs. HFD: 7.83 ± 0.16] and noradrenaline (pD2 E+ in CD: 6.36 ± 0.06 vs. HFD: 5.29 ± 0.06; pD2 E- in CD: 6.11 ± 0.08 vs. HFD: 5.80 ± 0.08) was found. Noradrenaline desensitized the angiotensin II response (pD2 with noradrenaline pretreatment in E+: 7.03 ± 0.16; in E-: 7.10 ± 0.02), but angiotensin II did not change the noradrenaline response. Acetylcholine maximal relaxation and basal nitric oxide (NO) release were comparable in both diet groups. The efficacy of angiotensin II (Rmax CD: 4604 ± 574 mg vs. HFD: 3251 ± 533 mg) and noradrenaline (Rmax CD: 11,675 ± 804 mg vs. HFD: 7975 ± 960 mg) was reduced in E+. L-N-nitroarginine methyl ester (L-NAME) recovered the efficacy of noradrenaline (Rmax L-NAME: 12,015 ± 317 mg). In contrast, L-NAME had no effect on the angiotensin II response. Noradrenaline enhanced NO levels, but angiotensin II did not. Therefore, NO was associated with hyporeactivity to noradrenaline. The resting potential was more negative in E+, and the endothelium diminished the angiotensin II-induced depolarization. These findings demonstrated that the crosstalk and the endothelium may induce hyporeactivity to angiotensin II and noradrenaline as a mechanism to compensate the increase in the blood pressure in HFD-induced obesity.
本研究旨在探讨血管紧张素 II 和去甲肾上腺素的血管反应性及其与高脂饮食喂养的兔子内皮功能的关系。动物分别喂食高脂饮食（HFD）或常规饲料[对照饮食（CD）]。12 周后，喂食 HFD 的兔子血压、体重和胰岛素水平升高。葡萄糖耐量受损且与血压呈正相关。血管紧张素 II 敏感性的内皮非依赖性降低[CD 中完整内皮主动脉环（E+）的 pD2：8.02 ± 0.07 对 HFD：7.60 ± 0.01；CD 中去除内皮的主动脉环（E-）的 pD2：8.16 ± 0.11 对 HFD：7.83 ± 0.16]和去甲肾上腺素（CD 中 pD2 E+：6.36 ± 0.06 对 HFD：5.29 ± 0.06；CD 中 pD2 E-：6.11 ± 0.08 对 HFD：5.80 ± 0.08）。发现去甲肾上腺素使血管紧张素 II 反应脱敏（E+中用去甲肾上腺素预处理的 pD2：7.03 ± 0.16；E-中 pD2：7.10 ± 0.02），但血管紧张素 II 不改变去甲肾上腺素的反应。两组饮食的乙酰胆碱最大松弛和基础一氧化氮（NO）释放相当。血管紧张素 II（Rmax CD：4604 ± 574 mg 对 HFD：3251 ± 533 mg）和去甲肾上腺素（Rmax CD：11675 ± 804 mg 对 HFD：7975 ± 960 mg）在 E+中的效力降低。L-N-硝基精氨酸甲酯（L-NAME）恢复了去甲肾上腺素的效力（Rmax L-NAME：12015 ± 317 mg）。相反，L-NAME 对血管紧张素 II 的反应没有影响。去甲肾上腺素增强了 NO 水平，但血管紧张素 II 没有。因此，NO 与去甲肾上腺素的低反应性有关。E+中的静息电位更负，内皮减少了血管紧张素 II 诱导的去极化。这些发现表明，细胞间通讯和内皮可能会导致血管紧张素 II 和去甲肾上腺素的低反应性，作为补偿 HFD 诱导肥胖时血压升高的机制。
