Central neuronal activation and pressor responses induced by circulating ANG II: role of the brain aldosterone-“ouabain” pathway

Abstract

An increase in plasma ANG II causes neuronal activation in hypothalamic nuclei and a slow pressor response, presumably by increasing sympathetic drive. We evaluated whether the activation of a neuromodulatory pathway, involving aldosterone and "ouabain," is involved in these responses. In Wistar rats, the subcutaneous infusion of ANG II at 150 and 500 ng x kg(-1) x min(-1) gradually increased blood pressure up to 60 mmHg at the highest dose. ANG II at 500 ng x kg(-1) x min(-1) increased plasma ANG II by 4-fold, plasma aldosterone by 25-fold, and hypothalamic aldosterone by 3-fold. The intracerebroventricular infusion of an aldosterone synthase (AS) inhibitor prevented the ANG II-induced increase in hypothalamic aldosterone without affecting the increase in plasma aldosterone. Neuronal activity, as assessed by Fra-like immunoreactivity, increased transiently in the subfornical organ (SFO) but progressively in the paraventricular nucleus (PVN) and supraoptic nucleus (SON). The central infusion of the AS inhibitor or a mineralocorticoid receptor blocker markedly attenuated the ANG II-induced neuronal activation in the PVN but not in the SON. Pressor responses to ANG II at 150 ng x kg(-1) x min(-1) were abolished by an intracerebroventricular infusion of the AS inhibitor. Pressor responses to ANG II at 500 ng x kg(-1) x min(-1) were attenuated by the central infusion of the AS inhibitor or the mineralocorticoid receptor blocker by 70-80% and by Digibind (to bind "ouabain") by 50%. These results suggest a novel central nervous system mechanism for the ANG II-induced slow pressor response, i.e., circulating ANG II activates the SFO, leading to the direct activation of the PVN and SON, and, in addition, via aldosterone-dependent amplifying mechanisms, causes sustained activation of the PVN and thereby hypertension.

Trimethylamine-N-Oxide: A Carnitine-Derived Metabolite That Prolongs the Hypertensive Effect of Angiotensin II in Rats

“…In contrast, chronic infusion of Ang II at a dose of 50 ng × min -1 have been shown to produce sustained borderline hypertension 13 , 17 or the lack of significant hemodynamic effects 18 . In the present study rats infused with Ang II at the lower dose showed a significantly increase in SBP and DBP for the first 5 days of infusion, followed by return of their BP to baseline level.…”

“…We decided to use a low-dose Ang II infusion protocol because rats infused with a high-dose Ang II show strong hypertensive response 13,14 , and it has been shown that animals with high blood pressure fail to respond to pressor compounds 15,16 . We found that infusion of Ang II alone significantly increased BP for the first 5 days of infusion, while the concomitant infusion of Ang II and TMAO produced sustained increase in BP, which suggests that TMAO prolonged the hypertensive effect of Ang II.…”

“…Since the hypertensive effect of combined treatment with Ang II and TMAO appeared after 5 days of infusions, it may be hypothesized that the effect was caused rather by long-term Ang II-dependent mechanisms such as an increase in blood volume or an increase in sympathetic drive due to the activation of central mechanisms involved in BP control 13,21 . This notion may also be supported by our preliminary experiments in which we found that short, 30-seconds-long IV infusions of TMAO at a dose of 1 to 12 mmol × s -1 did not affect resting BP and hypertensive effects of Ang II in rats (data not presented).…”

“…Besides, to achieve subpressor effect of Ang II we infused rats with low dose Ang II, while the number of studies on the effects of chronic low dose Ang II on BP is limited and the results are inconsistent 13,18 . Further research including an evaluation of water-electrolyte balance and the activity of sympathetic nervous system and the renin-angiotensin-aldosterone system is needed to provide mechanistic explanation for our findings.…”

Oxidative stress exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation in rats with hypertension induced by angiotensin II

“…The purpose of the present study was to test this hypothesis. In rats, we chronically stimulated the RAAS by an exogenous infusion of ANG II for 14 days to develop experimental hypertension (16,27,29,55). This model was used to focus on the physiological roles played by increased RAAS activity in the pathological characteristics of hypertension.…”