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Aims: The rostral ventrolateral medulla (RVLM) is the main sympathetic output of the central nervous system to control blood pressure. Reportedly, reactive oxygen species (ROS) can increase arterial pressure, leading to hypertension. As ROS increase the sympathetic tone in RVLM and obese animals present grater oxidative stress, it would be important to note this relationship., Main Methods: Therefore, we evaluated the systemic and central effects (in the RVLM) of vitamin C (vit C, an antioxidant) on the redox balance and cardiovascular and autonomic profiles in hyperadipose male rats. We also evaluated the neurotransmission by L-glutamate (L-glu) and vit C in the RVLM of awake hyperadipose rats., Key Findings: Our study confirmed that hyperadipose rats were hypertensive and tachycardic, presented increased sympathetic and decreased parasympathetic modulation of the heart, and had increased plasma lipoperoxidation compared with the control rats (CTR). Oral vitamin C treatment reverted cardiovascular, autonomic, and plasma redox dysfunction. Hyperadipose rats presented a higher blood pressure increase after L-glu microinjection and a lower response to vit C in the RVLM compared with the CTR group. Biochemical analysis of redox balance in RVLM punches showed that hyperadipose rats have increased NBT and T-BARS, and after treatment with vit C, the oxidative profile decreased. The antioxidative activity of vit C reduced the amount of ROS in the RVLM area that might have resulted in lowered blood pressure and sympathetic modulation., Significance: Our data suggest central and peripheral benefits of vit C treatment on cardiovascular, autonomic, and oxidative dysfunctions in hyperadipose animals., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We sought to investigate whether RVLM iNOS activity and oxidative profile may participate in the reduction of sympathetic responsiveness in swimming trained normotensive rats. Sedentary (S) and swimming trained (T) Wistar male rats chronically instrumented with an arterial catheter and guide cannula into the RVLM were submitted to continuous pressure and heart rate (HR) recordings and determination of autonomic control (power spectral analysis) before and after unilateral RVLM iNOS inhibition (aminoguanidine, 250 pmol/100 nL). Other S and T rats received local l-glutamate microinjection (5 nmol/100 nL). In separate S and T groups not submitted to brainstem cannulation, fresh bilateral RVLM punchs were collected for iNOS gene expression (qPCR); reduced glutathione and lipid peroxidation quantification (spectrophotometry); iron-reducing antioxidant (FRAP) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTS˙ + ) scavenger assays. iNOS gene expression was confirmed in fixed RVLM slices (immunofluorescence). T rats exhibited resting bradycardia, lower sympathovagal balance, reduced RVLM iNOS gene/protein expression and higher antioxidant capacity. Decreased iNOS expression was positively correlated with reduced HR. Pressor and tachycardic response to l-Glutamate were smaller in T rats. Aminoguanidine microinjection reduced sympathetic activity in S rats but did not change it in T rats expressing reduced RVLM iNOS content. Our data indicate that iNOS, expressed in the RVLM of normotensive male rats, has tonic effects on sympathetic activity and that swimming training is an efficient tool to reduce iNOS expression and augment the antioxidant defense, thus reducing glutamatergic responsiveness and sympathetic drive to cardiovascular effectors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We evaluated the cardiovascular effects of nitric oxide (NO) inhibitors microinjected into the rostral ventrolateral medulla (RVLM) of conscious rats. Application of L-NAME or aminoguanidine (AG) induced an increase in arterial blood pressure (MAP) and an increase in heart rate, whereas 7-nitroindazole (7-NI) decreased MAP and HR. Microinjection of glutamate produced an increase in MAP which was followed by either a tachycardia or a bradycardia. Such responses were blocked totally by prior administration of L-NAME and attenuated (approximately 50%) by 7-NI. In contrast, glutamate responses were enhanced by following AG. We conclude that in conscious rats, NO has tonic effects in the RVLM and may participate in the modulation of the actions of glutamate through iNOS and nNOS pathways.

The cardiovascular effects of microinjection of the amino acids glutamate and glycine within the rostral ventrolateral medulla (RVLM) after swimming training (ST) in unrestrained awake rats were investigated. Unilateral microinjection of l-glutamate (5, 20 and 50 mM, in 100 nl) produced a dose dependent increase in mean arterial pressure (MAP) in control (C) (16+/-5 mm Hg; 29+/-6 mm Hg; 43+/-6 mm Hg) and swim (SW) (1+/-1 mm Hg; 16+/-2 mm Hg; 25+/-3 mm Hg) groups. However, the magnitude of this response was lower in the swim group. Prazosin injection produced hypotension and tachycardia in both groups (C=-43+/-3 mm Hg/98+/-16 bpm; SW=-61+/-5 mm Hg/115+/-32 bpm). In the SW group the hypotension caused by prazosin was greater compared to C group, but the tachycardia was not different between them. After prazosin, glutamate response in RVLM was blocked in both groups as well. When glycine (10 mM or 1 M, in 100 nl) were microinjected into the RVLM of C group we observed two different effects: decrease in MAP with the lower dose and an increase in MAP with the higher dose (10 mM=-13+/-2 mm Hg; 1 M=47+/-6 mm Hg). However, after ST the hypertensive response to glycine was blunted with no alterations in the hypotensive response (10 mM=-14+/-1 mm Hg; 1 M=18+/-4 mm Hg). These findings suggest that RVLM is involved in the modulation of the sympathetic outflow to the cardiovascular system during exercise training.

A well-known action of nitric oxide (NO) is to stimulate the soluble form of guanylyl cyclase, evoking an accumulation of cyclic GMP in target cells. The aim of the present study was to examine the effects of inhibition of guanylyl cyclase dependent on NO during cardiovascular responses induced by L-glutamate and S-nitrosoglutathione (SNOG) microinjected into the rostral ventrolateral medulla (RVLM) of awake rats. Three days before the experiments, adult male Wistar rats (280 to 320 g) were anesthetized for implantation of guide cannulas to the desired stereotaxic position (AP=-2.5 mm, L=1.8 mm) in relation to lambda. The cannulas were fixed to the skull with acrylic cement. Twenty-four hours before the experiments, a femoral artery and vein were cannulated for recording arterial pressure (AP) and heart rate (HR) and injection of anesthetic. Unilateral microinjections (100 nL) of L-glutamate (5 nmol/L) and SNOG (2.5 nmol/L) were made into the histologically confirmed RVLM. The cardiovascular responses to these drugs were evaluated before and after microinjection (3 nmol/L, 200 nL) of either methylene blue or oxodiazoloquinoxaline (ODQ). The hypertensive effect of L-glutamate was attenuated by 74% after methylene blue (DeltaAP=49+/-8 to 13+/-4 mm Hg) and by 80.5% after ODQ (DeltaAP=30+/-2 to 6+/-2 mm Hg). The increase in AP produced by SNOG was fully blocked by ODQ (DeltaAP=39+/-8 to 1+/-2 mm Hg). These data indicate that cyclic GMP mechanisms have a key role in glutamatergic neurotransmission in the RVLM of awake rats, and it is most probable that NO participates in this response.

The aim of the present study was to examine the participation of NO in the rostral ventrolateral medulla (RVLM) of freely moving rats. We utilized NO donors and L-arginine, which were microinjected into the RVLM. Unilateral microinjection (100 nL) of 2.5 nmol sodium nitroprusside produced a biphasic response consisting of an initial, rapid increase in arterial pressure (AP) from 125+/-5 to 161+/-8 mm Hg (P<.01) and a second, long-lasting response with a progressive increase in AP (maximum delta peak, 34+/-9 mm Hg; P<.01). Another NO donor, S-nitroso-N-acetylpenicillamine (SNAP; 2.5 nmol), also produced immediate hypertension from 118+/-5 mm Hg to 168+/-7 mm Hg (P<.01) but without the second, long-lasting response. L-Arginine (5, 24, and 140 nmol) produced a gradual increase in AP. L-Glutamate (5 nmol) microinjected into the RVLM produced an increase in AP from 122+/-9 mm Hg to 171+/-8 mm Hg (P<.01) and bradycardia from 342+/-10 to 315+/-8 beats/min. This AP response was significantly attenuated, from 115+/-7 to 128+/-9 mm Hg (P<.05), after microinjection of methylene blue (3 nmol) without alterations in heart rate. These results indicate that NO may have an excitatory effect on the RVLM of freely moving rats, probably in association with glutamatergic synapses via cGMP mechanisms.

In this study we determined the cardiovascular effects produced by microinjection of angiotensin peptides [Angiotensin-(1-7) and Angiotensin II] and angiotensin antagonists (losartan, L-158,809, CGP 42112A. Sar1-Thr8-Ang II, A-779) into the rostral ventrolateral medulla of freely moving rats. Microinjection of angiotensins (12.5-50 pmol) produced pressor responses associated to variable changes in heart rate, usually tachycardia. Unexpectedly, microinjection of both AT1 and AT2 ligands produced pressor effects at doses that did not change blood pressure in anesthetized rats. Conversely, microinjection of Sar1-Thr8-Ang II and the selective Ang-(1-7) antagonist, A-779, produced a small but significant decrease in MAP an HR. These findings suggest that angiotensins can influence the tonic activity of vasomotor neurons at the RVLM. As previously observed in anesthetized rats, our results further suggest a role for endogenous Ang-(1-7) at the RVLM. The pressor activity of the ligands for AT1 and AT2 angiotensin receptor subtypes at the RVLM, remains to be clarified.