It is well known that breathing introduces rhythmical oscillations in the heart rate and arterial pressure levels. Sympathetic oscillations coupled to the respiratory activity have been suggested as an important homeostatic mechanism optimizing tissue perfusion and blood gas uptake/delivery. This respiratory-sympathetic coupling is strengthened in conditions of blood gas challenges (hypoxia and hypercapnia) as a result of the synchronized activation of brainstem respiratory and sympathetic neurons, culminating with the emergence of entrained cardiovascular and respiratory reflex responses. Studies have proposed that the ventrolateral region of the medulla oblongata is a major site of synaptic interaction between respiratory and sympathetic neurons. However, other brainstem regions also play a relevant role in the patterning of respiratory and sympathetic motor outputs. Recent findings suggest that the neurons of the nucleus of the solitary tract (NTS), in the dorsal medulla, are essential for the processing and coordination of respiratory and sympathetic responses to hypoxia. The NTS is the first synaptic station of the cardiorespiratory afferent inputs, including peripheral chemoreceptors, baroreceptors and pulmonary stretch receptors. The synaptic profile of the NTS neurons receiving the excitatory drive from afferent inputs is complex and involves distinct neurotransmitters, including glutamate, ATP and acetylcholine. In the present review we discuss the role of the NTS circuitry in coordinating sympathetic and respiratory reflex responses. We also analyze the neuroplasticity of NTS neurons and their contribution for the development of cardiorespiratory dysfunctions, as observed in neurogenic hypertension, obstructive sleep apnea and metabolic disorders.

The data demonstrated that moderate intensity RT prevented obesity-induced cardiovascular disorders simultaneously with reduced inflammatory responses and modifications of RAS in the NTS.

Aldosterone acting on the brain stimulates sodium appetite and sympathetic activity by mechanisms that are still not completely clear. In the present study, we investigated the effects of chronic infusion of aldosterone and acute injection of the mineralocorticoid receptor (MR) antagonist RU 28318 into the fourth ventricle (4th V) on sodium appetite. Male Wistar rats (280-350 g) with a stainless-steel cannula in either the 4th V or lateral ventricle (LV) were used. Daily intake of 0.3 M NaCl increased to 46 ± 15 and 130 ± 6 ml/24 h after 6 days of infusion of 10 and 100 ng/h of aldosterone into the 4th V (intake with vehicle infusion: 2 ± 1 ml/24 h). Water intake fell slightly and not consistently, and food intake was not affected by aldosterone. Sodium appetite induced by diuretic (furosemide) combined with 24 h of a low-sodium diet fell from 12 ± 1.7 ml/2 h to 5.6 ± 0.8 ml/2 h after injection of the MR antagonist RU 28318 (100 ng/2 μl) into the 4th V. RU 28318 also reduced the intake of 0.3 M NaCl induced by 9 days of a low-sodium diet from 9.5 ± 2.6 ml/2 h to 1.2 ± 0.6 ml/2 h. Infusion of 100 or 500 ng/h of aldosterone into the LV did not affect daily intake of 0.3 M NaCl. The results are functional evidence that aldosterone acting on MR in the hindbrain activates a powerful mechanism involved in the control of sodium appetite.

Previous studies showed that leptin-deficient (ob/ob) mice develop obesity and impaired ventilatory responses to CO2 (trueV.normalE − CO2). In this study, we examined if leptin replacement improves chemorespiratory responses to hypercapnia (7 % CO2) in ob/ob mice and if these effects were due to changes in body weight or to the direct effects of leptin in the central nervous system (CNS). trueV.normalE−CO2 was measured via plethysmography in obese leptin-deficient- (ob/ob) and wild-type-(WT) mice before and after leptin (10 μg/2 μl day) or vehicle (phosphate buffer solution) were microinjected into the fourth ventricle for four consecutive days. Although baseline trueV.normalE was similar between groups, obese ob/ob mice exhibited attenuated trueV.normalE−CO2 compared to WT mice (134±9 versus 196±10 ml min−1). Fourth ventricle leptin treatment in obese ob/ob mice significantly improved trueV.normalE−CO2 (from 131 ± 15 to 197 ± 10 ml min−1) by increasing tidal volume (from 0.38±0.03 to 0.55±0.02 ml, vehicle and leptin, respectively). Subcutaneous leptin administration at the same dose administered centrally did not change trueV.normalE−CO2 in ob/ob mice. Central leptin treatment in WThad no effect on trueV.normalE−CO2. Since the fourth ventricle leptin treatment decreased body weight in ob/ob mice, we also examined trueV.normalE−CO2 in lean pair-weighted ob/ob mice and found it to be impaired compared to WT mice. Thus, leptin deficiency, rather than obesity, is the main cause of impaired trueV.normalE−CO2 in ob/ob mice and leptin appears to play an important role in regulating chemorespiratory response by its direct actions on the CNS.

Aim Leptin, an adipocyte-derived hormone, is suggested to participate in the central control of breathing. We hypothesized that leptin may facilitate ventilatory responses to chemoreflex activation by acting on respiratory nuclei of the ventrolateral medulla. The baseline ventilation and the ventilatory responses to CO2 were evaluated before and after daily injections of leptin into the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) for 3 days in obese leptin-deficient (ob/ob) mice. Methods Male ob/ob mice (40–45 g, n = 7 per group) received daily microinjections of vehicle or leptin (1 μg per 100 nL) for 3 days into the RTN/pFRG. Respiratory responses to CO2 were measured by whole-body plethysmography. Results Unilateral microinjection of leptin into the RTN/pFRG in ob/ob mice increased baseline ventilation (VE) from 1447 ± 96 to 2405 ± 174 mL min−1 kg−1 by increasing tidal volume (VT) from 6.4 ± 0.4 to 9.1 ± 0.8 mL kg−1 (P < 0.05). Leptin also enhanced ventilatory responses to 7% CO2 (Δ = 2172 ± 218 mL min−1 kg−1, vs. control: Δ = 1255 ± 105 mL min−1 kg−1), which was also due to increased VT (Δ = 4.71 ± 0.51 mL kg−1, vs. control: Δ = 2.27 ± 0.20 mL kg−1), without changes in respiratory frequency. Leptin treatment into the RTN/pFRG or into the surrounding areas decreased food intake (83 and 70%, respectively), without significantly changing body weight. Conclusion The present results suggest that leptin acting in the respiratory nuclei of the ventrolateral medulla improves baseline VE and VT and facilitates respiratory responses to hypercapnia in ob/ob mice.

Melanocortin receptors (MC3/4R) mediate most of the metabolic and cardiovascular actions of leptin. Aim here we tested if MC4R also contributes to leptin’s effects on respiratory function. Methods after control measurements, male Holtzman rats received daily microinjections of leptin, SHU9119 (MC3/4R antagonist) or SHU9119 combined with leptin infused into the brain lateral ventricle for 7 days. On the 6th day of treatment, tidal volume (VT), respiratory frequency (fR) and pulmonary ventilation (VE) were measured by whole-body plethysmography during normocapnia or hypercapnia (7% CO2). Baseline mean arterial pressure (MAP), heart rate (HR) and metabolic rate were also measured. VE, VT and fR were also measured in mice with leptin receptor deletion in the entire central nervous system (LepR/Nestin-cre) or only in proopiomelanocortin neurons (LepR/POMC-cre) and in MC4R knockout (MC4R−/−) and wild-type mice. Results leptin (5 μg/day) reduced body weight (~17%) and increased ventilatory response to hypercania, whereas SHU9119 (0.6 nmol/day) increased body weight (~18%) and reduced ventilatory responses compared to control-PBS group (Lep: 2119 ± 90 ml.min−1.kg−1and SHU9119: 997 ± 67 ml.min−1.kg−1, vs PBS: 1379 ± 91 ml.min−1.kg−1). MAP increased after leptin treatment (130 ± 2 mmHg) compared to PBS (106 ± 3 mmHg) or SHU9119 alone (109 ± 3 mmHg). SHU9119 prevented the effects of leptin on body weight, MAP (102 ± 3 mmHg) and ventilatory response to hypercania (1391 ±137 ml.min−1.kg−1). The ventilatory response to hypercania was attenuated in the LepR/Nestin-cre, LepR/POMC-cre and MC4R−/− mice. Conclusion these results suggest that central MC4R mediate the effects of leptin on respiratory response to hypercapnia.

We examined whether central melanocortin 3 and 4 receptor (MC3/4R) blockade attenuates the BP responses to chronic L-NAME or angiotensin II (Ang-II) infusion in Sprague Dawley rats implanted with telemetry transmitters, venous catheters and intracerebroventricular (ICV) cannula into the lateral ventricle. After 5 days of control measurements, L-NAME (10 μg/kg/day, i.v. – groups 1 and 2) or Ang II (10 ng/kg/min, i.v. – groups 3 and 4) were infused for 24 days and starting on day 7 of L-NAME or Ang II infusion the MC3/4R antagonist SHU-9119 (24 nmol/day, n=6/group – groups 1 and 3) or vehicle (saline 0.5 μl/hr, n=6/group – groups 2 and 4) was infused ICV for 10 days. A control normotensive group also received SHU-9119 for 10 days (n=5). L-NAME and Ang II increased BP by 40±3 and 56±5 mmHg, respectively; while heart rate (HR) was slightly reduced. MC3/4R blockade doubled food intake and reduced HR (~40 to ~50 bpm) in all groups. MC3/4R blockade caused only a small reduction in BP in normotensive group (4 mmHg) and no change in rats receiving Ang II, while markedly reducing BP by 21±4 mmHg in L-NAME treated rats. After SHU-9119 infusion was stopped, food intake, HR and BP gradually returned to values observed before SHU-9119 infusion was started. Ganglionic blockade performed at the end of L-NAME or Ang II infusion caused similar BP reduction in both groups. These results suggest that the brain MC3/4R contributes, at least in part, to the hypertension induced by chronic L-NAME infusion but not by Ang II.

New Findings r What is the central question of this study?Is sympathorespiratory activity affected in a different manner by cholinergic mechanisms in the intermediate (iNTS) and commissural nucleus of the solitary tract (cNTS) and are cholinergic mechanisms involved in baro-and chemoreflexes? r What is the main finding and its importance? Acetylcholine (ACh) injected into the iNTS promotes sympatho-inhibition and reduces the phrenic frequency, whereas ACh injected into the cNTS increases phrenic frequency and affects sympathetic-respiratory coupling, without changing the sympathetic activity. These responses are abolished by mecamylamine (nicotinic antagonist) in the NTS. Mecamylamine in the cNTS also reduces peripheral chemoreflex-induced tachypnoea.The contribution of cholinergic mechanisms of the nucleus of the solitary tract (NTS) to cardiorespiratory control is not completely clear. In the present study, we investigated the involvement of the cholinergic mechanisms in the intermediate NTS (iNTS) and commissural NTS (cNTS) on the control of sympathetic (SNA) and phrenic nerve activity (PNA). Decorticated, arterially perfused in situ preparations of male juvenile rats (60-100 g) were used. Acetylcholine (10 mm, 60 nl) injected into the iNTS reduced SNA (−54 ± 4%, versus vehicle −5 ± 3%; P < 0.001) and PNA (−30 ± 4%, versus vehicle −5 ± 6%; P < 0.001), whereas injections of ACh into the cNTS increased PNA (30 ± 6%, versus vehicle 5 ± 3%; P < 0.001), without changing SNA. Pretreatment with mecamylamine (nicotinic antagonist; 5 mm) abolished all the effects of ACh injected into the iNTS or the cNTS, whereas atropine (muscarinic antagonist; 5 mm) reduced only the effects of ACh injected into the cNTS. Mecamylamine injected into the cNTS also reduced the tachypnoea in response to peripheral chemoreflex activation. The baroreflex was unaltered by injections of atropine or mecamylamine into the NTS. The results suggest that ACh and mainly nicotinic receptors in the NTS are involved in the modulation of SNA and PNA, with distinct functions between the iNTS and the cNTS. An involvement of the nicotinic receptors in the cNTS in the tachypnoea in response to peripheral chemoreflex activation is also suggested.