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(Circulation Research. 2005;97:772.)
© 2005 American Heart Association, Inc.

Integrative Physiology

NADPH Oxidase–Derived Superoxide Anion Mediates Angiotensin II–Induced Pressor Effect via Activation of p38 Mitogen–Activated Protein Kinase in the Rostral Ventrolateral Medulla

Samuel H.H. Chan, Kuei-Sen Hsu, Chiung-Chun Huang, Ling-Lin Wang, Chen-Chun Ou, Julie Y.H. Chan

From the Center for Neuroscience, National Sun Yat-sen University (S.H.H.C.), Kaohsiung; Department of Pharmacology, National Cheng Kung University (K.S.H., C.C.H.), Tainan; and Department of Medical Education and Research, Kaohsiung Veterans General Hospital (L.L.W., C.C.O., J.Y.H.C.), Kaohsiung, Taiwan, Republic of China.

Correspondence to Julie Y.H. Chan, PhD, Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Taiwan 813, Republic of China. E-mail yhwa{at}isca.vghks.gov.tw

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.

Key Words: mitogen-activated protein kinases • angiotensin II • superoxide anion • NADPH oxidase • rostral ventrolateral medulla • blood pressure

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