title: Activation of central PPAR-γ attenuates angiotensin II-induced hypertension.
abstract: 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.
authors.affiliation: 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.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: 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.).
authors.forename: Bao-Jian
authors.initials: BJ
authors.lastname: Xue
authors.affiliation: 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.).
authors.forename: Shun-Guang
authors.initials: SG
authors.lastname: Wei
authors.affiliation: 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.).
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Terry G
authors.initials: TG
authors.lastname: Beltz
authors.affiliation: 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.).
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.affiliation: 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.).
authors.forename: Alan Kim
authors.initials: AK
authors.lastname: Johnson
authors.affiliation: 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.). robert-felder@uiowa.edu.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Felder
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D057967:Infusions, Intraventricular; D055104:Infusions, Subcutaneous; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D047495:PPAR gamma; D045162:Thiazolidinediones; D000804:Angiotensin II; D000077205:Pioglitazone
keywords: angiotensin II; brain; inflammation; peroxisome proliferator-activated receptors; renin-angiotensin system