Background-The paraventricular nucleus of the hypothalamus (PVN) has emerged as one of the most important autonomic control centers in the brain, with neurons playing essential roles in controlling stress, metabolism, growth, reproduction, immune, and other more traditional autonomic functions (gastrointestinal, renal and cardiovascular).Objectives-Traditionally the PVN was viewed very much as a nucleus in which afferent inputs from other regions were faithfully translated into changes in single specific outputs whether those were neuroendocrine or autonomic. Here we will present data which suggest that PVN in fact plays significant and essential roles in integrating multiple sources of afferent input and sculpting an integrated autonomic output by concurrently modifying the excitability of multiple output pathways. In addition we will highlight recent work which suggests that dysfunction of such intranuclear integrative circuitry may contribute to the pathology of conditions such as hypertension and congestive heart failure.Conclusions-This review highlights data showing that individual afferent inputs (SFO), signaling molecules (orexins, adiponectin), and interneurons (glutamate/GABA), all have the potential to influence (and thus coordinate) multiple PVN output pathways. We also highlight recent studies showing that modifications in this integrated circuitry may play significant roles in the pathology of diseases such as congestive heart failure and hypertension.

In this review we present the case for both hormonal and neurotransmitter actions of angiotensin II (ANG) In the control of neuronal excitability In a simple neural pathway involved In central autonomic regulation. We will present both single-ceil and whole-animal data highlighting hormonal roles for ANG In controlling the excitability of subfornical organ (SFO) neurons. More controversially we will also present the case for a neurotransmitter role for ANG in SFO neurons in controlling the excitability of Identified neurons In the paraventricular nucleus (PVN)of the hypothalamus. In this review we highlight the similarities between the actions of ANG on these two populations of neurons in an attempt to emphasize that whether we call such actions "hormonal" or "neurotransmitter" is largely semantic. In fact such definitions oniy refer to the method of delivery of the chemical messenger, in this case ANG, to Its cellular site of action, In this case the AT 1 receptor. We also described In this review some novel concepts that may underlie synthesis, metabOlic processing, and co-transmitter actions of ANG In this pathway. We hope that such suggestions may lead ultimately to the development of broader gUiding principles to enhance our understanding of the mUltiplicity of physiological uses for single chemical messengers.

The hypothalamic paraventricular nucleus (PVN) has been shown to play major obligatory roles in autonomic and neuroendocrine regulation. Angiotensin II (ANG) acts as a neurotransmitter regulating the excitability of magnocellular neurons in this nucleus. We report here that ANG also activates a nitric-oxide-mediated negative feedback loop in the PVN that acts to regulate the functional output of magnocellular neurons. Thus in addition to its depolarizing actions on magnocellular neurons, ANG application results in an increase in the frequency of inhibitory postsynaptic potentials in a population of these neurons without effect on the amplitude of these events. ANG was also without significant effect on the mean frequency or amplitude of mini synaptic currents analyzed in voltage-clamp experiments. This increase in inhibitory input after ANG can be abolished by the nitric oxide synthase inhibitor Nomega-nitro-l-arginine methylester, demonstrating a requisite role for nitric oxide in the activation of this pathway. The depolarization of magnocellular neurons that show increased inhibitory postsynaptic potential (IPSP) frequency in response to ANG is significantly smaller than that observed in neurons in which IPSPs frequency was unaffected (3.2 +/- 1.1 vs. 8.0 +/- 0.5 mV, P< 0.05). Correspondingly, after nitric oxide synthase inhibition, the depolarizing effects of ANG on magnocellular neurons are augmented (2.0 +/- 0.7 vs. 6.7 +/- 0.7 mV, P < 0.05). The depolarization was also enhanced in the presence of the GABAergic antagonist bicuculline (1.9 +/- 1.2 vs. 11.9 +/- 2.3, P < 0.001). These data demonstrate that there exists within the PVN an intrinsic negative feedback loop that modulates neuronal excitability in response to peptidergic excitation.