title: Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines.
abstract: The renin-angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5μg/h) or vehicle for 4weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy.
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China. Electronic address: ykang@mail.xjtu.edu.cn.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Kang
authors.affiliation: Department of Physiology, Dalian Medical University, Dalian 116044, China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Yu
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Su
authors.affiliation: Department of Obstetrics and Gynecology, Shanxi Provincial People's Hospital, Taiyuan 030012, China.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Suo
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Yue
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Zhu
authors.affiliation: Department of Physiology, Shantou University Medical College, Shantou 515041, China. Electronic address: dnqin@stu.edu.cn.
authors.forename: Da-Nian
authors.initials: DN
authors.lastname: Qin
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy*; D018932:Chemokine CCL2 / Q000378:metabolism; D015773:Enalaprilat / Q000008:administration & dosage / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000097:blood; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy*; D016753:Interleukin-10 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000097:blood
chemical_list: D018932:Chemokine CCL2; D053583:Interleukin-1beta; D015850:Interleukin-6; D018377:Neurotransmitter Agents; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D016753:Interleukin-10; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat; D019808:Losartan; D009638:Norepinephrine
keywords: Angiotensin-converting enzyme; Cardiac hypertrophy; Cytokines; Hypertension; Hypothalamic paraventricular nucleus; Neurotransmitters