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.

Gabor A, Leenen FHH. Mechanisms in the PVN mediating local and central sodium-induced hypertension in Wistar rats.

No abstract

A chronic increase in circulating angiotensin II (Ang II) increases neuronal activation in hypothalamic nuclei, such as the paraventricular nucleus (PVN), 1,2 and causes progressive hypertension, 2,3 presumably by increasing sympathetic activity. [4][5][6] A central neuromodulatory pathway involving aldosterone-endogenous ouabain (EO) seems to play a critical role in these responses to Ang II. 2,7 Chronic subcutaneous infusion of Ang II increases plasma and hypothalamic aldosterone content. 2 Intracerebroventricular infusion of an aldosterone synthase (AS) inhibitor prevents increase in hypothalamic, but not in plasma aldosterone, and intracerebroventricular infusion of an AS inhibitor or a mineralocortoicod receptor (MR) blocker markedly attenuate the neuronal activation in the PVN.2 Intracerebroventricular infusion of an AS inhibitor, 2 MR blocker, 2,7 EO-binding antibody Fab fragments (Digibind), 2 or an angiotensin type 1 (AT 1 )-receptor blocker 8 largely prevents the Ang II-induced hypertension. These findings suggest that a chronic increase in circulating Ang II increases local hypothalamic aldosterone production, and activates an MR-EO pathway in the brain, which is essential for the Ang II-induced hypertension.Several models of chronic sympathetic hyperactivity are associated with an increase in glutamate receptor and AT 1 -receptor activation in the PVN. A glutamate or AT 1 -receptor blocker in the PVN decreases sympathetic nerve activity, blood pressure (BP), and heart rate (HR) in rats with chronic heart failure 9,10 and in spontaneously hypertensive rats. 11 Glutamate and AT 1 -receptor blockers in the PVN decrease BP in waterdeprived rats 12 and in Dahl S rats on high-salt diet. 13 In Dahl S rats on a high-salt diet, at the peak BP decrease by a glutamate receptor blocker, an AT 1 -receptor blocker in the PVN does not further decrease BP. 13 These findings suggest that the effects of increased AT 1 -receptor activation in the PVN of hypertensive Dahl S rats are fully mediated by local glutamate release. Consistent with these findings, Ang II increases glutamatergic signaling in the PVN, either by increasing glutamate release from interneurons, 14,15 or by decreasing gamma-amino butyric acid (GABA)-mediated inhibition of the PVN. 16,17 No studies have yet evaluated the role of the central aldosterone neuromodulatory pathway in Ang II and glutamate receptor activation in the PVN of hypertensive rats. We hypothesized Abstract-A chronic increase in circulating angiotensin II (Ang II) activates an aldosterone-mineralocorticoid receptorouabain neuromodulatory pathway in the brain that increases neuronal activation in hypothalamic nuclei, such as the paraventricular nucleus (PVN) and causes progressive hypertension. Several models of chronic sympathetic hyperactivity are associated with an increase in AT 1 and glutamate receptor activation in the PVN. The current study evaluated whether increased angiotensin type 1 (AT 1 ) and glutamate receptor-dependent signaling in the PVN contributes to the mainten...

Intracerebroventricular infusion of Na(+)-rich artificial cerebrospinal fluid (aCSF) causes larger sympathetic and pressor responses in Dahl salt-sensitive (S) than -resistant (R) or Wistar rats. Enhanced activity of the aldosterone-"ouabain" pathway or decreased nitric oxide (NO) release may contribute to this enhanced responsiveness. Where in the brain these mechanisms interact is largely unknown. The present study evaluated whether Na(+) in the paraventricular nucleus (PVN) causes larger pressor responses in Dahl S (SS/Mcw) than R (Dahl SS.BN13) rats and whether mineralocorticoid receptors, benzamil-blockable Na(+) channels, "ouabain," angiotensin type 1 receptors, or NO mediates these enhanced responses. Na(+)-rich aCSF in the PVN caused 30-40% larger increases in blood pressure and heart rate in Dahl S than R or Wistar rats, whereas responses to ouabain, ANG II, or N(ω)-nitro-l-arginine methyl ester hydrochloride (l-NAME) in the PVN were the same. These responses to Na(+) were not affected by eplerenone, benzamil, or Fab fragments, whereas they were fully blocked by losartan, in Dahl S and R rats. l-NAME enhanced them more in Dahl R than S rats, thereby equalizing the responses in the two strains. Pressor responses to l-NAME in the PVN were attenuated by a high-salt diet in Dahl S, but not R, rats. The results indicate that acute and chronic increases in Na(+) concentration in the PVN inhibit NO release in the PVN of Dahl S, but not R, rats, thereby contributing to the enhanced pressor responses to Na(+) in Dahl S rats.