Angiotensin II type 2 receptor-coupled nitric oxide production modulates free radical availability and voltage-gated Ca 2+ currents in NTS neurons

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2012-05, Vol.302 (9), p.R1076-R1083
• Main Authors: Wang, Gang, Coleman, Christal G., Glass, Michael J., Zhou, Ping, Yu, Qi, Park, Laibaik, Anrather, Josef, Pickel, Virginia M., Iadecola, Costantino
• Format: Article
• Language: English
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00571.2011

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.