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Toxicol Appl Pharmacol. 2014 Feb 1;274(3):436-44. doi: 10.1016/j.taap.2013.12.001. Epub 2013 Dec 14.

Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines.

Author information

1
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.
2
Department of Physiology, Dalian Medical University, Dalian 116044, China.
3
Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
4
Department of Obstetrics and Gynecology, Shanxi Provincial People's Hospital, Taiyuan 030012, China.
5
Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
6
Department of Physiology, Shantou University Medical College, Shantou 515041, China. Electronic address: dnqin@stu.edu.cn.

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.

KEYWORDS:

Angiotensin-converting enzyme; Cardiac hypertrophy; Cytokines; Hypertension; Hypothalamic paraventricular nucleus; Neurotransmitters

PMID:
24342267
DOI:
10.1016/j.taap.2013.12.001
[Indexed for MEDLINE]

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