The medial region of the nucleus tractus solitarius (mNTS) is a key brainstem site controlling cardiovascular function, wherein angiotensin II (AngII) modulates neuronal L-type Ca2+ currents via activation of AngII type 1 receptors (AT1R) and production of reactive oxygen species (ROS). AngII type 2 receptors (AT2R) induce production of nitric oxide (NO), which may interact with ROS and modulate AT1R signaling. We sought to determine whether AT2R-mediated NO production occurs in mNTS neurons and, if so, to elucidate the NO source and the functional interaction with AT1R-induced ROS or Ca2+ influx. Electron microscopic (EM) immunolabeling showed that AT2R and neuronal NO synthase (nNOS) are co-expressed in neuronal somata and dendrites receiving synapses in the mNTS. In the presence of the AT1R antagonist losartan, AngII increased NO production in isolated mNTS neurons, an effect blocked by the AT2R 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. AngII-induced ROS production was enhanced by PD123319, the NOS inhibitor nitro-L-arginine (LNNA), or in nNOS-null mice. Moreover, in the presence of losartan, AngII reduced voltage-gated L-type Ca2+ current, an effect blocked by PD123319 or LNNA. We conclude that AT2R are closely associated and functionally coupled with nNOS in mNTS neurons. The resulting NO production antagonizes AT1R-mediated ROS and dampens L-type Ca2+ currents. The ensuing signaling changes in the NTS may counteract the deleterious effects of AT1R on cardiovascular function.
- Nitric oxide
- autonomic function
- blood pressure
- voltage-gated Ca2+ channels
- Copyright © 2011, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology