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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.)

Oxytocinergic brainstem projections participate in the autonomic control of the circulation. We investigated the effects of hypertension and training on cardiovascular parameters after oxytocin (OT) receptor blockade within the nucleus tractus solitarii (NTS) and NTS OT and OT receptor expression. Male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were trained (55% of maximal exercise capacity) or kept sedentary for 3 months and chronically instrumented (NTS and arterial cannulae). Mean arterial blood pressure (MAP) and heart rate (HR) were measured at rest and during an acute bout of exercise after NTS pretreatment with vehicle or OT antagonist (20 pmol of OT antagonist (200 nl of vehicle)(-1)). Oxytocin and OT receptor were quantified ((35)S-oligonucleotide probes, in situ hybridization) in other groups of rats. The SHR exhibited high MAP and HR (P < 0.05). Exercise training improved treadmill performance and reduced basal HR (on average 11%) in both groups, but did not change basal MAP. Blockade of NTS OT receptor increased exercise tachycardia only in trained groups, with a larger effect on trained WKY rats (+31 +/- 9 versus +12 +/- 3 beats min(1) in the trained SHR). Hypertension specifically reduced NTS OT receptor mRNA density (-46% versus sedentary WKY rats, P < 0.05); training did not change OT receptor density, but significantly increased OT mRNA expression (+2.5-fold in trained WKY rats and +15% in trained SHR). Concurrent hypertension- and training-induced plastic (peptide/receptor changes) and functional adjustments (HR changes) of oxytocinergic control support both the elevated basal HR in the SHR group and the slowing of the heart rate (rest and exercise) observed in trained WKY rats and SHR.

It is now well established that brain plasticity is an inherent property not only of the developing but also of the adult brain. Numerous beneficial effects of exercise, including improved memory, cognitive function and neuroprotection, have been shown to involve an important neuroplastic component. However, whether major adaptive cardiovascular adjustments during exercise, needed to ensure proper blood perfusion of peripheral tissues, also require brain neuroplasticity, is presently unknown. This review will critically evaluate current knowledge on proposed mechanisms that are likely to underlie the continuous resetting of baroreflex control of heart rate during/after exercise and following exercise training. Accumulating evidence indicates that not only somatosensory afferents (conveyed by skeletal muscle receptors, baroreceptors and/or cardiopulmonary receptors) but also projections arising from central command neurons (in particular, peptidergic hypothalamic pre-autonomic neurons) converge into the nucleus tractus solitarii (NTS) in the dorsal brainstem, to co-ordinate complex cardiovascular adaptations during dynamic exercise. This review focuses in particular on a reciprocally interconnected network between the NTS and the hypothalamic paraventricular nucleus (PVN), which is proposed to act as a pivotal anatomical and functional substrate underlying integrative feedforward and feedback cardiovascular adjustments during exercise. Recent findings supporting neuroplastic adaptive changes within the NTS-PVN reciprocal network (e.g. remodelling of afferent inputs, structural and functional neuronal plasticity and changes in neurotransmitter content) will be discussed within the context of their role as important underlying cellular mechanisms supporting the tonic activation and improved efficacy of these central pathways in response to circulatory demand at rest and during exercise, both in sedentary and in trained individuals. We hope this review will stimulate more comprehensive studies aimed at understanding cellular and molecular mechanisms within CNS neuronal networks that contribute to exercise-induced neuroplasticity and cardiovascular adjustments.

We investigate whether arterial baroreceptors mediate the training-induced blood pressure fall and resting bradycardia in hypertensive (SHR) and normotensive rats (WKY). Male SHR and WKY rats, submitted to sino-aortic denervation (SAD) or sham surgery (SHAM group), were allocated to training (T; 55% of maximal exercise capacity) or sedentary (S) protocols for 3 months. Rats were instrumented with arterial and venous catheters for haemodynamic measurements at rest (power spectral analysis) and baroreceptor testing. Kidney and skeletal muscles were processed for morphometric analysis of arterioles. Elevated mean arterial pressure (MAP) and heart rate (HR) in SHAM SHRS were accompanied by increased sympathetic variability and arteriolar wall/lumen ratio [+3.4-fold on low-frequency (LF) power and +70%, respectively, versus WKYS, P < 0.05]. Training caused significant HR (approximately 9% in WKY and SHR) and MAP reductions (-8% in the SHR), simultaneously with improvement of baroreceptor reflex control of HR (SHR and WKY), LF reduction (with a positive correlation between LF power and MAP levels in the SHR) and normalization of wall/lumen ratio of the skeletal muscle arterioles (SHR only). In contrast, SAD increased pressure variability in both strains of rats, causing reductions in MAP (-13%) and arteriolar wall/lumen ratio (-35%) only in the SHRS. Training effects were completely blocked by SAD in both strains; in addition, after SAD the resting MAP and HR and the wall/lumen ratio of skeletal muscle arterioles were higher in SHRT versus SHRS and similar to those of SHAM SHRS. The lack of training-induced effects in the chronic absence of baroreceptor inputs strongly suggests that baroreceptor signalling plays a decisive role in driving beneficial training-induced cardiovascular adjustments.

Previous work demonstrated that oxytocinergic projections to the solitary vagal complex are involved in the restraint of exercise-induced tachycardia (2). In the present study, we tested the idea that oxytocin (OT) terminals in the solitary vagal complex [nucleus of the solitary tract (NTS)/dorsal motor nucleus of the vagus (DMV)] are involved in baroreceptor reflex control of heart rate (HR). Studies were conducted in male rats instrumented for chronic cardiovascular monitoring with a cannula in the NTS/DMV for brain injections. Basal mean arterial pressure and HR and reflex HR responses during loading and unloading of the baroreceptors (phenylephrine/sodium nitroprusside intravenously) were recorded after administration of a selective OT antagonist (OT(ant)) or OT into the NTS/DMV. The NTS/DMV was selected for study because this region contains such a specific and dense concentration of OT-immunoreactive terminals. Vehicle injections served as a control. OT and OT(ant) changed baroreflex control of HR in opposite directions. OT (20 pmol) increased the maximal bradycardic response (from -56 +/- 9 to -75 +/- 11 beats/min), whereas receptor blockade decreased the bradycardia (from -61 +/- 13 to -35 +/- 2 beats/min). OT(ant) also reduced the operating range of the reflex, thus decreasing baroreflex gain (from -5.68 +/- 1.62 to -2.83 +/- 1.05 beats x min(-1) x mmHg(-1)). OT injected into the NTS/DMV of atenolol-treated rats still potentiated the bradycardic responses to pressor challenges, whereas OT injections had no effect in atropine-treated rats. The brain stem effect was specific because neither vehicle administration nor injection of OT or OT(ant) into the fourth cerebral ventricle had any effect. Our data suggest that OT terminals in the solitary vagal complex modulate reflex control of the heart, acting to facilitate vagal outflow and the slowdown of the heart.

Objective: Toinvestigate the modulatory effect of endogenous nitric oxide (NO) in the nucleus tractus solitarii (NTS) on the baroreceptor reflex control of heart rate in conscious spontaneously hypertensive (SHR) and normotensive (WKY) rats., Design and Methods: Male age- and weight-matched SHR and WKY chronically instrumented with cannulas in the NTS, artery and vein were used. Basal pressure (AP), heart rate (HR) and reflex HR responses during loading/unloading of baroreceptors (phenylephrine/sodium nitroprusside, iv) were recorded during vehicle (3 nl/min) NG-monomethyl-L-arginine (L-NMMA) and L-arginine (L-Arg) infusions into the NTS. Constitutive NO synthase (NOS) activity was inferred by 3H-citrulline formation in the dorsal brain stem of other SHR and WKY groups., Results: In SHR a small dose of L-NMMA (30 ng/kg/min) restricted to the NTS did not change AP and HR (185+/-4 mmHg, 373+/-12 beats/min, respectively), but decreased the HR range (57+/-7 beats/min, a 34% reduction, P< 0.05) without changing further the impaired gain of baroreceptor reflex control of HR. In the WKY group similar results (significant 32% reduction in HR range, gain unchanged) were only attained with a dose 10 times higher (L-NMMA(NTS) = 300 ng/kg/min), no effect being observed with the small dose (HR range = 163+/-12 beats/min). In SHR, L-Arg(NTS) (900 ng/kg/min) did not improve baroreflex control of HR, but restored the depression of HR range when given after L-NMMA(NTS). Basal NOS activity in the dorsal brain stem was reduced in SHR (P < 0.05) when compared to WKY group., Conclusions: NO modulates, at the NTS level, the baroreceptor reflex control of HR in both SHR and WKY not by altering the gain, but by increasing HR range during afferent stimulation. In SHR the depressed NO modulation is in accordance with the smaller NOS activity in the dorsal brain stem.

The present article contains a brief review on the role of vasopressinergic projections to the nucleus tractus solitarii in the genesis of reflex bradycardia and in the modulation of heart rate control during exercise. The effects of vasopressin on exercise tachycardia are discussed on the basis of both the endogenous peptide content changes and the heart rate response changes observed during running in sedentary and trained rats. Dynamic exercise caused a specific vasopressin content increase in dorsal and ventral brainstem areas. In accordance, rats pretreated with the peptide or the V1 blocker into the nucleus tractus solitarii showed a significant potentiation or a marked blunting of the exercise tachycardia, respectively, without any change in the pressure response to exercise. It is proposed that the long-descending vasopressinergic pathway to the nucleus tractus solitarii serves as one link between the two main neural controllers of circulation, i.e., the central command and feedback control mechanisms driven by the peripheral receptors. Therefore, vasopressinergic input could contribute to the adjustment of heart rate response (and cardiac output) to the circulatory demand during exercise.

Our objective was to study the role of vasopressinergic synapses at the nucleus tractus solitarii (NTS) in the modulation of exercise-induced tachycardia. We evaluated the effect of NTS administration of vasopressin (AVP) or vasopressin antagonist (AVP(ant)) on heart rate (HR) and mean arterial pressure (MAP) responses during dynamic exercise in male rats with chronic arterial and NTS cannulas. Sedentary (S) and trained (T) animals were tested at three or four exercise levels (from 0.4 up to 1.4 km/h) after NTS injection of AVP or AVP(ant) 20-30 min before treadmill exercise. Plasma and regional brain levels of AVP were measured in separate groups of S and T rats at rest and immediately after acute exercise. When administered into the NTS, exogenous AVP (20 pmol) caused a small but significant decrease in baseline HR and potentiated the tachycardiac response to mild to moderate exercise intensities (on average, increases of 35-46 beats/min over control tachycardic response). The potentiation of exercise tachycardia by AVP was long lasting and more pronounced in T than in S rats. Even 2 days after NTS AVP injection, there was evidence for an alteration in the HR response to exercise. Mediation by V1 receptors was supported by the blunted tachycardiac response to exercise after administration of a V1 antagonist d(CH2)5Tyr MeAVP into the NTS in both T and S rats (average reductions of 23-34 and 13-19 beats/min below control tachycardia, respectively). No changes were observed in baseline MAP or the exercise-induced pressor responses. There were specific changes in brain stem AVP levels that were related to the exercise treatment. T rats showed a marked increase in dorsal and ventral brain stem AVP content after acute exercise. There were no changes in hypothalamus, median eminence, posterior pituitary, or plasma AVP. These data indicate that vasopressinergic synapses and V1 receptors in the NTS are involved in the potentiation of tachycardic response to exercise. The vasopressinergic mechanism operates in both S and T rats, but training alters the sensitization of V1 receptors by AVP.

To assess the role of angiotensin (ANG) II in both the increased heart rate (HR) and the impaired baroreceptor reflex control of HR that characterize the chronic phase of coarctation hypertension (CH), we compared basal HR, mean arterial pressure (MAP), and baroreflex sensitivity of coarcted hypertensive rats treated chronically with losartan, captopril, or vehicle. Baseline HR was recorded daily, and MAP and reflex HR changes and plasma renin activity (PRA) were measured in coarcted and sham-coarcted rats on the 5th day after coarctation. Both captopril (10 mg.kg-1.day-1 po) and losartan (10 mg.kg-1.day-1 po) caused a small nonsignificant reduction of hypertension (132 +/- 5 and 133 +/- 5, respectively, vs. 147 +/- 9 mmHg in vehicle-treated rats), but equally inhibited the late tachycardic phase (-37 +/- 13 and -29 +/- 12 beats/min in captopril- and losartan-treated groups, respectively, vs. +79 +/- 19 beats/min in vehicle treated rats). Similar results were obtained for other groups of coarcted hypertensive rats after suppression of PRA by bilateral nephrectomy. Although hypertensive levels were the same during both treatments, only losartan given orally or intracerebroventricularlly (1.25 micrograms.kg-1.h-1) was effective in improving the reflex bradycardia. The depressed reflex tachycardia was corrected by chronic oral treatment with losartan. The data suggest that the tachycardia occurring in the chronic phase of CH is mediated by blood-borne ANG II and that the normalization of the reflex control of HR by losartan is achieved by blockade of type I receptors of ANG II in central areas accessible to oral or centrally administered losartan but not to oral captopril.

1. The main role of the nucleus tractus solitarius (NTS) as a relay center for viscerosensory fibers from the periphery and for pathways from modulatory autonomic centers is reviewed on the basis of its anatomical connections and neurotransmitter content. 2. Vasopressin is present in the entire neuroaxis and is of great importance in the control of cardiovascular function. The high endogenous content and receptor density, and the unique organization of vasopressin fibers projecting to the NTS are fundamental features for the modulatory effect exerted by vasopressin at the NTS on the baroreceptor reflex control of heart rate. 3. Vasopressinergic pathways from the paraventricular nucleus of the hypothalamus to the NTS constitute a physiological mechanism for the tonic maintenance of the baroreflex sensitivity and for displacing the heart rate response to higher values during increased activity, without changing the baroreflex sensitivity. This type of mechanism should play an important role in facilitating the tachycardic response during isotonic exercise.

To determine whether the central vasopressinergic system at the level of nucleus tractus solitarii (NTS) modulates the reflex control of heart rate, we employed a new method for microinjection into the brainstem of conscious, freely moving rats. Baroreceptor reflex function was assessed during pressure changes induced by intravenous administration of phenylephrine (0.25-8 micrograms/kg) and sodium nitroprusside (0.5-16 micrograms/kg) in rats microinjected, through a permanent cannula into the brainstem, with saline, arginine vasopressin (AVP), or an AVP blocker. Baseline levels of pressure and heart rate were not changed by either peptide pretreatment. Restricted injection of AVP (20 ng-0.2 microliter) into the NTS attenuated the reflex bradycardia during pressure increases, with an upward displacement of the baroreceptor reflex function line (p less than 0.01) without change in the sensitivity. Local blockade of endogenous AVP, d(CH2)5Tyr(Me)AVP (1 microgram-0.2 microliter), depressed baroreceptor reflex sensitivity with intense bradycardia to either small or large pressure increases. Baroreceptor reflex control of heart rate in response to decreases in pressure was preserved during pretreatment with AVP, whereas endogenous blockade of AVP increased baroreceptor reflex sensitivity. These effects were specific to the NTS, since in another four rats there were no effects when the injections were made 1 mm above, into the cerebellum. The changes in baroreceptor reflex control of heart rate in conscious, unrestrained rats caused by administration of AVP and its endogenous blockade provide evidence that central vasopressinergic synapses at the NTS are important physiological modulators of baroreceptor reflex function.