Central neuromodulatory pathways regulating sympathetic activity in hypertension.

The classical neurotransmitters, glutamate and GABA, mediate fast (milliseconds) synaptic transmission and modulate its effectiveness through slow (seconds to minutes) signaling processes. Angiotensinergic pathways, from the lamina terminalis to the paraventricular nucleus (PVN)/supraoptic nucleus and rostral ventrolateral medulla (RVLM), are activated by stimuli such as circulating angiotensin type II (Ang II), cerebrospinal fluid (CSF) sodium ion concentration ([Na(+)]), and possibly plasma aldosterone, leading to sympathoexcitation, largely by decreasing GABA and increasing glutamate release. The aldosterone-endogenous ouabain (EO) pathway is a much slower neuromodulatory pathway. Aldosterone enhances EO release, and the latter increases chronic activity in angiotensinergic pathways by, e.g., increasing expression for Ang I receptor (AT(1)R) and NADPH oxidase subunits in the PVN. Blockade of this pathway does not affect the initial sympathoexcitatory and pressor responses but to a large extent, prevents chronic responses to CSF [Na(+)] or Ang II. Recruitment of these two neuromodulatory pathways allows the central nervous system (CNS) to shift gears to rapidly cause and sustain sympathetic hyperactivity in an efficient manner. Decreased GABA release, increased glutamate release, and enhanced AT(1)R activation in, e.g., the PVN and RVLM contribute to the elevated blood pressure in a number of hypertension models. In Dahl S rats and spontaneous hypertensive rats, high salt activates the CNS aldosterone-EO pathway, and the salt-induced hypertension can be prevented/reversed by specific CNS blockade of any of the steps in the cascade from aldosterone synthase to AT(1)R. Further studies are needed to advance our understanding of how and where in the brain these rapid, slow, and very slow CNS pathways are activated and interact in models of hypertension and other disease states associated with chronic sympathetic hyperactivity.