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 (O 2 ⅐Ϫ ) 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 (AT 1 ) 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 AT 1 receptor-dependent increase in O 2 ⅐Ϫ 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 AT 1 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 O 2 ⅐Ϫ 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. (Circ Res. 2005;97:772-780.)Key Words: mitogen-activated protein kinases Ⅲ angiotensin II Ⅲ superoxide anion Ⅲ NADPH oxidase Ⅲ rostral ventrolateral medulla Ⅲ blood pressure I n addition to its well-known actions on the vasculature, angiotensin II (Ang II) also plays a critical role in central regulation of circulatory functions. 1,2 One brain target where Ang II exerts its influence on cardiovascular control is rostral ventrolateral medulla (RVLM), 3,4 where premotor neurons that maintain tonic sympathetic vasomotor outflow are located. 5 The RVLM contains a high density of Ang II receptors 6 and is a major site of the sympathoexcitatory and pressor actions of the octapeptide. 7,8 It is generally accepted that activation of Ang II type 1 (AT 1 ) receptors in the RVLM contributes mainly to the cardiovascular effects of Ang II. 9,10 The reactive oxygen species, particularly superoxide anion (O 2 ⅐Ϫ ), is an important intracellular messenger for brain Ang II. The octapeptide increases the activity of NADPH oxidase, the major source of O 2 ⅐Ϫ in the vasculature, 11 and enhances O 2 ⅐Ϫ production in the central nervous system. 12,13 Intracerebroventricular infusion of NADPH oxidase inhibitor antagonizes the increase in renal sympa...

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The striatum is a crucial site of action for the motor effects of cannabinoids (CBs). However, the electrophysiological consequences of activation of CB receptors on the striatal neurons have not been established. Here we report for the first time that the cannabimimetic aminoalkylindole WIN 55,212‐2 and the endogenous cannabinoid anandamide substantially depress corticostriatal glutamatergic synaptic transmission onto striatal neurons in the brain slice preparation. The selective CB1 receptor antagonist SR 141716 effectively reversed this inhibition. WIN 55,212‐2 significantly increased the paired‐pulse facilitation of synaptically evoked EPSCs, while having no effect on the sensitivity of postsynaptic neurons to α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid. WIN 55,212‐2 also reduced the frequency of spontaneous, action potential‐dependent EPSCs (sEPSCs) without altering their amplitude distribution. Superfusion of WIN 55,212‐2 elicited a membrane hyperpolarization accompanied by a decrease in input resistance. Both effects were blocked by intracellular caesium. In contrast, intracellular caesium failed to affect WIN 55,212‐2‐mediated synaptic inhibition. The WIN 55,212‐2‐mediated synaptic inhibition was blocked by the Gi/o protein inhibitor pertussis toxin (PTX), but not by the GABAA receptor antagonist bicuculline or GABAB receptor antagonist SCH 50911. Pretreatment with the N‐type Ca2+ channel antagonist ω‐conotoxin GVIA selectively abolished the WIN‐55,212‐2‐mediated synaptic inhibition. These results suggest that cannabinoids depress the corticostriatal glutamatergic synaptic transmission through the activation of presynaptic CB1 receptors to inhibit N‐type Ca2+ channel activity, which in turn reduces glutamate release. The presynaptic action of cannabinoids is mediated by a PTX‐sensitive Gi/o protein‐coupled signalling pathway.