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Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines.
Toxicol Appl Pharmacol. 2014 Feb 01; 274(3):436-44.TA

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+Show Affiliations

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.Department of Physiology, Dalian Medical University, Dalian 116044, China.Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.Department of Obstetrics and Gynecology, Shanxi Provincial People's Hospital, Taiyuan 030012, China.Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029, China.Department of Physiology, Shantou University Medical College, Shantou 515041, China. Electronic address: dnqin@stu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24342267

Citation

Kang, Yu-Ming, et al. "Chronic Infusion of Enalaprilat Into Hypothalamic Paraventricular Nucleus Attenuates Angiotensin II-induced Hypertension and Cardiac Hypertrophy By Restoring Neurotransmitters and Cytokines." Toxicology and Applied Pharmacology, vol. 274, no. 3, 2014, pp. 436-44.
Kang YM, Zhang DM, Yu XJ, et al. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines. Toxicol Appl Pharmacol. 2014;274(3):436-44.
Kang, Y. M., Zhang, D. M., Yu, X. J., Yang, Q., Qi, J., Su, Q., Suo, Y. P., Yue, L. Y., Zhu, G. Q., & Qin, D. N. (2014). Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines. Toxicology and Applied Pharmacology, 274(3), 436-44. https://doi.org/10.1016/j.taap.2013.12.001
Kang YM, et al. Chronic Infusion of Enalaprilat Into Hypothalamic Paraventricular Nucleus Attenuates Angiotensin II-induced Hypertension and Cardiac Hypertrophy By Restoring Neurotransmitters and Cytokines. Toxicol Appl Pharmacol. 2014 Feb 1;274(3):436-44. PubMed PMID: 24342267.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines. AU - Kang,Yu-Ming, AU - Zhang,Dong-Mei, AU - Yu,Xiao-Jing, AU - Yang,Qing, AU - Qi,Jie, AU - Su,Qing, AU - Suo,Yu-Ping, AU - Yue,Li-Ying, AU - Zhu,Guo-Qing, AU - Qin,Da-Nian, Y1 - 2013/12/14/ PY - 2013/08/27/received PY - 2013/11/21/revised PY - 2013/12/01/accepted PY - 2013/12/18/entrez PY - 2013/12/18/pubmed PY - 2014/3/22/medline KW - Angiotensin-converting enzyme KW - Cardiac hypertrophy KW - Cytokines KW - Hypertension KW - Hypothalamic paraventricular nucleus KW - Neurotransmitters SP - 436 EP - 44 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 274 IS - 3 N2 - 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. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/24342267/Chronic_infusion_of_enalaprilat_into_hypothalamic_paraventricular_nucleus_attenuates_angiotensin_II_induced_hypertension_and_cardiac_hypertrophy_by_restoring_neurotransmitters_and_cytokines_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(13)00548-6 DB - PRIME DP - Unbound Medicine ER -