Central Ang II (Angiotensin II)-Mediated Sympathoexcitation

Abstract

Central infusion of Ang II (angiotensin II) has been associated with increased sympathetic outflow resulting in neurogenic hypertension. In the present study, we appraised whether the chronic increase in central Ang II activates the paraventricular nucleus of the hypothalamus (PVN) resulting in elevated sympathetic tone and altered baro- and chemoreflexes. Further, we evaluated the contribution of HIF-1α (hypoxia-inducible factor-1α), a transcription factor involved in enhancing the expression of N-methyl-D-aspartate receptors and thus glutamatergic-mediated sympathetic tone from the PVN. Ang II infusion (20 ng/minute, intracerebroventricular, 14 days) increased mean arterial pressure (126±9 versus 84±4 mm Hg), cardiac sympathetic tone (96±7 versus 75±6 bpm), and decreased cardiac parasympathetic tone (16±2 versus 36±3 versus bpm) compared with saline-infused controls in conscious rats. The Ang II-infused group also showed an impaired baroreflex control of heart rate (−1.50±0.1 versus −2.50±0.3 bpm/mm Hg), potentiation of the chemoreflex pressor response (53±7 versus 30±7 mm Hg) and increased number of FosB-labeled cells (53±3 versus 19±4) in the PVN. Concomitant with the activation of the PVN, there was an increased expression of HIF-1α and N-Methyl-D-Aspartate-type1 receptors in the PVN. Further, Ang II-infusion showed increased renal sympathetic nerve activity (20.5±2.3% versus 6.4±1.9% of Max) and 3-fold enhanced renal sympathetic nerve activity responses to microinjection of N-methyl-D-aspartate (200 pmol) into the PVN of anesthetized rats. Further, silencing of HIF-1α in NG108 cells abrogated the expression of N-methyl-D-aspartate-N-methyl-D-aspartate-type1 induced by Ang II. Taken together, our studies suggest a novel Ang II-HIF-1α-N-methyl-D-aspartate receptor-mediated activation of preautonomic neurons in the PVN, resulting in increased sympathetic outflow and alterations in baro- and chemoreflexes.

Central Administration of Hydrogen Sulfide Donor NaHS Reduces Iba1-Positive Cells in the PVN and Attenuates Rodent Angiotensin II Hypertension

“…We have previously shown that HR can decrease with age in normotensive rodents ( Zubcevic et al, 2009 ). Thus, attenuation of these time-dependent changes in HF IBI and HR in the Ang II group suggests deregulation of cardiac parasympathetic drive after Ang II infusion, as it has previously been reported ( Miller and Arnold, 2019 ; Dorey et al, 2020 ; Sharma et al, 2021 ). However, this effect of Ang II on HF IBI was not significantly affected by ICV NaHS co-treatments, suggesting lesser effects of central infusion of NaHS on parasympathetic control of BP in our study.…”

Lactacystin-induced kidney fibrosis: Protection by melatonin and captopril

“…In line with this, surprisingly, lactacystin did not reduce but increased blood pressure and fibrotic rebuilding in the left ventricle (Simko et al, 2017). Thus, lactacystin administration-induced BP elevation was recently characterized as a novel model of experimental hypertension (Vrankova et al, 2010;Simko et al, 2017;Sharma et al, 2020). Proteasome inhibition may cause hypertension either because of an increased endogenous protein inhibitor of neuronal nitric oxide synthase, leading to decreased NO bioavailability in the paraventricular nucleus (Sharma et al, 2020), or from tyrosine hydroxylase upregulation and activation in the hypothalamus and brainstem (Congo Carbajosa et al, 2015), both resulting in increased sympathetic outflow.…”

“…Thus, lactacystin administration-induced BP elevation was recently characterized as a novel model of experimental hypertension (Vrankova et al, 2010;Simko et al, 2017;Sharma et al, 2020). Proteasome inhibition may cause hypertension either because of an increased endogenous protein inhibitor of neuronal nitric oxide synthase, leading to decreased NO bioavailability in the paraventricular nucleus (Sharma et al, 2020), or from tyrosine hydroxylase upregulation and activation in the hypothalamus and brainstem (Congo Carbajosa et al, 2015), both resulting in increased sympathetic outflow. Bearing in mind the remodeling of the heart (Simko et al, 2017) and aorta (Vrankova et al, 2010) in this model, it seems to be of importance to disclose whether lactacystin could act in a similar pro-proliferative way in hypertensive kidneys.…”

“…Chronic lactacystin administration induces a mild but significant rise in systolic blood pressure (BP) along with fibrotic remodeling of the left ventricle (LV) in Wistar rats (Simko et al, 2017), and hypertrophy of the aorta in L-NAME (L-NG-nitro arginine methyl ester)-induced hypertension (Vrankova et al, 2010). Several hypothetical mechanisms for hemodynamic alterations and heart and vessel damage by lactacystin have been proposed, such as enhanced oxidative stress (Vrankova et al, 2010;Huseby et al, 2016;Parajuli, 2019), decreased NO bioavailability (Simko et al, 2017;Sharma et al, 2020), sympathetic nervous system activation (Congo Carbajosa et al, 2015) and modification of various cytosolic, nuclear, and myofibrillar protein turnovers (Mearini et al, 2008). However, data on lactacystin's renal effects are not available.…”

The Regulatory Effect of the Paraventricular Nucleus on Hypertension

“…Chronic stress-induced persistent hypertension is mediated by an increased sympathetic outflow also through α-2δ-1-linked NMDARs in the PVN [81]. Hypoxia-inducible factor-1α participates in the Ang II-NMDAR-mediated activation of presympathetic neurons in the PVN by upregulating NMDAR expression, ulti-mately increasing sympathetic outflow [82]. Evidently, the RAS in the PVN independently exerts a pressor effect and synergistically interacts with other processes, such as oxidative stress and glutamatergic and GABAergic synapses.…”