title: NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla.
abstract: The rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons are located, is a central site via which angiotensin II (Ang II) elicits its pressor effect. We tested the hypothesis that NADPH oxidase-derived superoxide anion (O2*-) in the RVLM mediates Ang II-induced pressor response via activation of mitogen-activated protein kinase (MAPK) signaling pathways. Bilateral microinjection of Ang II into the RVLM resulted in an angiotensin subtype 1 (AT1) receptor-dependent phosphorylation of p38 MAPK and extracellular signal-regulated protein kinase (ERK)1/2, but not stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK), in the ventrolateral medulla. The Ang II-induced p38 MAPK or ERK1/2 phosphorylation was attenuated by application into the RVLM of a NADPH oxidase inhibitor, diphenyleneiodonium chloride (DPI), an antisense oligonucleotide that targets against p22phox or p47phox subunit of NADPH oxidase mRNA, or the superoxide dismutase mimetic tempol. DPI or antisense p22phox or p47phox oligonucleotide treatment also attenuated the AT1 receptor-dependent increase in O2*- production in the ventrolateral medulla elicited by Ang II at the RVLM. Functionally, Ang II-elicited pressor response in the RVLM was attenuated by DPI, tempol, or a p38 MAPK inhibitor, SB203580. The AT1 receptor-mediated enhancement of the frequency of glutamate-sensitive spontaneous excitatory postsynaptic currents induced by Ang II in RVLM neurons was also abolished by SB203580. These results suggest that NADPH oxidase-derived O2*- underlies the activation of p38 MAPK or ERK1/2 by Ang II in the ventrolateral medulla. Furthermore, the p38 MAPK signaling pathway may mediate Ang II-induced pressor response via enhancement of presynaptic release of glutamate to RVLM neurons.
authors.affiliation: Center for Neuroscience, National Sun Yat-sen University, Tainan, Taiwan, Republic of China.
authors.forename: Samuel H H
authors.initials: SH
authors.lastname: Chan
authors.forename: Kuei-Sen
authors.initials: KS
authors.lastname: Hsu
authors.forename: Chiung-Chun
authors.initials: CC
authors.lastname: Huang
authors.forename: Ling-Lin
authors.initials: LL
authors.lastname: Wang
authors.forename: Chen-Chun
authors.initials: CC
authors.lastname: Ou
authors.forename: Julie Y H
authors.initials: JY
authors.lastname: Chan
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000201:enzymology / Q000502:physiology*; D019255:NADPH Oxidases / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009861:Onium Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D007093:Imidazoles; D016376:Oligonucleotides, Antisense; D009861:Onium Compounds; D011725:Pyridines; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D013481:Superoxides; D000804:Angiotensin II; C073402:PD 123319; C007517:diphenyleneiodonium; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019808:Losartan