Journal article
Angiotensin II Triggered p44/42 Mitogen-Activated Protein Kinase Mediates Sympathetic Excitation in Heart Failure Rats
Hypertension (Dallas, Tex. 1979), Vol.52(2), pp.342-350
08/2008
DOI: 10.1161/HYPERTENSIONAHA.108.110445
PMCID: PMC2785116
PMID: 18574076
Abstract
Angiotensin II (ANG II), acting via angiotensin type 1 receptors (AT
1
-R) in the brain, activates the sympathetic nervous system in heart failure (HF). We recently reported that ANG II stimulates mitogen-activated protein kinase (MAPK) to upregulate brain AT
1
-R in HF rats. In this study we tested the hypothesis that ANG II-activated MAPK signaling pathways contribute to sympathetic excitation in HF. Intracerebroventricular (ICV) administration of PD98059 and UO126, two selective p44/42 MAPK inhibitors, induced significant decreases in mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in HF rats, but had no effect on these variables in SHAM rats. Pretreatment with losartan attenuated the effects of PD98059. ICV administration of the p38 MAPK inhibitor SB203580 and the c-Jun N-terminal kinase inhibitor SP600125 had no effect on MAP, HR or RSNA in HF. The phosphatidylinositol-3 kinase inhibitor LY294002 induced a small decrease in MAP and HR, but no change in RSNA. Immunofluorescent staining demonstrated increased p44/42 MAPK activity in neurons of the paraventricular nucleus of the hypothalamus (PVN) of HF rats, co-localized with Fra-like activity (indicating chronic neuronal excitation). ICV PD98059 and UO126 reduced Fra-like activity in PVN neurons in HF rats. In confirmatory acute studies, ICV ANG II increased MAP, HR and RSNA in baroreceptor-denervated rats and Fra-LI immunoreactivity in the PVN of neurally intact rats. Central administration of PD98059 markedly reduced these responses. These data demonstrate that intracellular p44/42 MAPK activity contributes to ANG II-induced PVN neuronal excitation and augmented sympathetic nerve activity in rats with HF.
Details
- Title: Subtitle
- Angiotensin II Triggered p44/42 Mitogen-Activated Protein Kinase Mediates Sympathetic Excitation in Heart Failure Rats
- Creators
- Shun-Guang Wei - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Yang Yu - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Zhi-Hua Zhang - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Robert M Weiss - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Robert B Felder - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.52(2), pp.342-350
- DOI
- 10.1161/HYPERTENSIONAHA.108.110445
- PMID
- 18574076
- PMCID
- PMC2785116
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Language
- English
- Date published
- 08/2008
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984065388502771
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