title: Angiotensin II type 2 receptor-coupled nitric oxide production modulates free radical availability and voltage-gated Ca2+ currents in NTS neurons.
abstract: The medial region of the nucleus tractus solitarius (mNTS) is a key brain stem site controlling cardiovascular function, wherein ANG II modulates neuronal L-type Ca(2+) currents via activation of ANG II type 1 receptors (AT(1)R) and production of reactive oxygen species (ROS). ANG II type 2 receptors (AT(2)R) induce production of nitric oxide (NO), which may interact with ROS and modulate AT(1)R signaling. We sought to determine whether AT(2)R-mediated NO production occurs in mNTS neurons and, if so, to elucidate the NO source and the functional interaction with AT(1)R-induced ROS or Ca(2+) influx. Electron microscopic (EM) immunolabeling showed that AT(2)R and neuronal NO synthase (nNOS) are coexpressed in neuronal somata and dendrites receiving synapses in the mNTS. In the presence of the AT(1)R antagonist losartan, ANG II increased NO production in isolated mNTS neurons, an effect blocked by the AT(2)R antagonist PD123319, but not the angiotensin (1-7) antagonist D-Ala. Studies in mNTS neurons of nNOS-null or endothelial NOS (eNOS)-null mice established nNOS as the source of NO. ANG II-induced ROS production was enhanced by PD123319, the NOS inhibitor N(G)-nitro-l-arginine (LNNA), or in nNOS-null mice. Moreover, in the presence of losartan, ANG II reduced voltage-gated L-type Ca(2+) current, an effect blocked by PD123319 or LNNA. We conclude that AT(2)R are closely associated and functionally coupled with nNOS in mNTS neurons. The resulting NO production antagonizes AT(1)R-mediated ROS and dampens L-type Ca(2+) currents. The ensuing signaling changes in the NTS may counteract the deleterious effects of AT(1)R on cardiovascular function.
authors.affiliation: Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York 10065, USA. gaw2001@med.cornell.edu
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Christal G
authors.initials: CG
authors.lastname: Coleman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Glass
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Qi
authors.initials: Q
authors.lastname: Yu
authors.forename: Laibaik
authors.initials: L
authors.lastname: Park
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Pickel
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002478:Cells, Cultured; D005609:Free Radicals / Q000378:metabolism; D015640:Ion Channel Gating / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism*; D017552:Solitary Nucleus / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D005609:Free Radicals; D011945:Receptors, Angiotensin; D009569:Nitric Oxide; D002118:Calcium