Yu Yang, Xue Bao-Jian, Wei Shun-Guang, Zhang Zhi-Hua, Beltz Terry G, Guo Fang, Johnson Alan Kim, Felder Robert B
From the Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine (Y.Y., S.-G.W., Z.-H.Z., R.B.F.) and Department of Psychological and Brain Sciences (B.-.J.X., T.G.B., F.G., A.K.J.), University of Iowa, Iowa City; and Research Service, Veterans Affairs Medical Center, Iowa City, IA (R.B.F.).
Hypertension. 2015 Aug;66(2):403-11. doi: 10.1161/HYPERTENSIONAHA.115.05726. Epub 2015 Jun 22.
Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that the activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg per minute) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA-binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2, and angiotensin II type 1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA-binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension.
大脑中的炎症和肾素-血管紧张素系统活性通过对液体摄入、血管加压素释放和交感神经活动的影响导致高血压。我们最近报道，心力衰竭大鼠脑内过氧化物酶体增殖物激活受体（PPAR）-γ的激活降低了下丘脑室旁核的炎症和肾素-血管紧张素系统活性，并改善了心力衰竭的外周表现。我们推测，脑PPAR-γ的激活可能对血管紧张素II诱导的高血压有有益作用。将Sprague-Dawley大鼠皮下输注血管紧张素II（每分钟120 ng/kg）2周，同时持续脑室内输注溶媒、PPAR-γ激动剂吡格列酮（3 nmol/h）或PPAR-γ拮抗剂GW9662（7 nmol/h）。血管紧张素II+溶媒组大鼠平均血压升高，对神经节阻滞的平均血压反应表明交感神经驱动力增加，水消耗增加。穹窿下器和下丘脑室旁核中的PPAR-γ mRNA未发生变化，但PPAR-γ DNA结合活性降低。两个核中白细胞介素-1β、肿瘤坏死因子-α、环氧化酶-2和血管紧张素II 1型受体的mRNA均增加，下丘脑室旁核神经元活性增强。对6小时限水的血浆血管加压素反应也增加。GW9662加剧了这些对血管紧张素II的反应，而吡格列酮改善了这些反应，吡格列酮增加了穹窿下器和下丘脑室旁核中的PPAR-γ mRNA和PPAR-γ DNA结合活性。吡格列酮和GW9662对对照大鼠无影响。结果表明，激活脑PPAR-γ以减轻中枢炎症和脑肾素-血管紧张素系统活性可能是治疗血管紧张素II依赖性高血压的有用辅助手段。
