Mirian Bassi

Hindbrain mineralocorticoid mechanisms on sodium appetite

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.

Control of respiratory and cardiovascular functions by leptin.

Leptin, a peptide hormone produced by adipose tissue, acts in brain centers that control critical physiological functions such as metabolism, breathing and cardiovascular regulation. The importance of leptin for respiratory control is evident by the fact that leptin deficient mice exhibit impaired ventilatory responses to carbon dioxide (CO2), which can be corrected by intracerebroventricular leptin replacement therapy. Leptin is also recognized as an important link between obesity and hypertension. Humans and animal models lacking either leptin or functional leptin receptors exhibit many characteristics of the metabolic syndrome, including hyperinsulinemia, insulin resistance, hyperglycemia, dyslipidemia and visceral adiposity, but do not exhibit increased sympathetic nerve activity (SNA) and have normal to lower blood pressure (BP) compared to lean controls. Even though previous studies have extensively focused on the brain sites and intracellular signaling pathways involved in leptin effects on food intake and energy balance, the mechanisms that mediate the actions of leptin on breathing and cardiovascular function are only beginning to be elucidated. This mini-review summarizes recent advances on the effects of leptin on cardiovascular and respiratory control with emphasis on the neural control of respiratory function and autonomic activity.

Leptin into the ventrolateral medulla facilitates chemorespiratory response in leptin-deficient (ob/ob) mice

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.

Activation of the brain melanocortin system is required for leptin-induced modulation of chemorespiratory function

Melanocortin receptors (MC3/4R) mediate most of the metabolic and cardiovascular actions of leptin.

Resistance training prevents the cardiovascular changes caused by high-fat diet

AIMS Aerobic exercise is indicated for prevention and treatment of obesity-induced cardiovascular disorders. Although the resistance training (RT) may also produce effects similar to aerobic exercise, this is not completely clear yet. In the present study, we tested if RT in moderate intensity might prevent alterations in blood pressure (BP), sympathetic modulation of systolic blood pressure (SBP), baroreflex function and the changes in renin-angiotensin system (RAS) and cytokines mRNA expression within the nucleus of the tract solitary (NTS) in rats fed with high-fat diet (HFD). MAIN METHODS Male Holtzman rats (300-320 g) were divided into 4 groups: sedentary with standard chow diet (SED-SD); sedentary with high-fat diet (SED-HFD); RT with standard chow diet (RT-SD); and RT with high-fat diet (RT-HFD). The trained groups performed a total of 10 weeks of moderate intensity RT in a vertical ladder. In the first 3 weeks all experimental groups were fed with SD. In the next 7 weeks, the SED-HFD and RT-HFD groups were fed with HFD. KEY FINDINGS In SED-HFD, BP and sympathetic modulation of SBP increased, whereas baroreflex bradycardic responses were attenuated. RT prevented the cardiovascular and inflammatory responses (increases in tumoral necrosis factor-α and interleukin-1β) produced by HFD in SED rats. The anti-inflammatory interleukin-10, angiotensin type 2 receptor, Mas receptor and angiotensin converting enzyme 2 mRNA expressions in the NTS increased in the RT-HFD compared to SED-HFD. SIGNIFICANCE The data demonstrated that moderate intensity RT prevented obesity-induced cardiovascular disorders simultaneously with reduced inflammatory responses and modifications of RAS in the NTS.

Long‐term facilitation of expiratory and sympathetic activities following acute intermittent hypoxia in rats

Acute intermittent hypoxia (AIH) promotes persistent increases in ventilation and sympathetic activity, referred as long‐term facilitation (LTF). Augmented inspiratory activity is suggested as a major component of respiratory LTF. In this study, we hypothesized that AIH also elicits a sustained increase in expiratory motor activity. We also investigated whether the expiratory LTF contributes to the development of sympathetic LTF after AIH.

Differential modulation of sympathetic and respiratory activities by cholinergic mechanisms in the nucleus of the solitary tract in rats

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? 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.

Respiratory Function in the South American Lungfish, Lepidosiren paradoxa

1. Respiratory properties of blood and pattern of branchial and pulmonary gas exchange have been studied in twelve specimens of the South American lungfish, Lepidosiren paradoxa (Fitz). 2. Haematocrit ranged from 14 to 19% and blood oxygen capacity from 4.9 to 6.8 vol. %. The blood had a high affinity for O2 with a P 50 value of 10.5 mm. Hg at P co2 6 mm. Hg and temperature 23° C. The Bohr effect was low. 3. The CO2 dissociation curves show a steep ascending slope resulting in a relatively high CO2 combining power at physiological values of blood P co2 The Haldane effect was small. Buffering capacity of oxygenated whole blood was high and exceeded that in typical water breathers. 4. Air breathing was prominent and intervals between air breaths varied from 3 to 10 min. Branchial respiratory movements were extremely shallow and showed a labile frequency. Air breathing was stimulated by hypoxic and hypercarbic water while hyperoxygenated water had no effect. Branchial respiratory rate showed a marked acceleration in response to mechanical agitation of the water. 5. Gas exchange was predominantly carried out by pulmonary breathing. In less than 10 min. the P O2 of expired gas dropped from 150 mm. Hg to less than 30 mm. Hg. The shallow branchial breathing with very low ventilation values resulted in a low O2 uptake via the gills. 6. Blood-gas analysis documented a clear selective passage of blood through the only partially divided heart. A consistently higher P O2 in dorsal aortic than in pulmonary arterial blood indicates a preferential passage of pulmonary venous blood to the anterior branchial arteries giving rise to most of the systemic circulation while systemic venous blood was largely conveyed to the most posterior branchial arteries giving rise to the pulmonary arteries. 7. The oxygen uptake for fish resting in water with access to air averaged 53.4 ml./hr./kg. Exposure to air lowered the O2 uptake markedly. 8. The increased importance of pulmonary breathing in Lepidosiren is discussed in relation to the transition from water breathing to air breathing. This investigation was supported by grant G.B. 358 from the National Science Foundation and grants H.E. 0845 and H.E. 01892 from the National Institute of Health. This work was carried out during the tenure of an Established Investigatorship of the American Heart Association.

DECREASED NEURON LOSS AND MEMORY DYSFUNCTION IN PILOCARPINE-TREATED RATS PRE-EXPOSED TO HYPOXIA

Preconditioning can induce a cascade of cellular events leading to neuroprotection against subsequent brain insults. In this study, we investigated the chronic effects of hypoxic preconditioning on spontaneous recurrent seizures (SRS), neuronal death, and spatial memory performance in rats subjected to pilocarpine (Pilo)-induced status epilepticus (SE). Rats underwent a short hypoxic episode (7% O2+93% N2; 30min on two consecutive days) preceding a 4-h SE (HSE group). Control groups were rats submitted to SE only (SE), rats subjected to hypoxia only (H) or normoxia-saline (C). Animals were monitored for the occurrence of SRS, and spatial memory performance was evaluated in the radial-arm maze. Hippocampal sections were analyzed for cell death and mossy fiber sprouting at 1 or 60days after SE. Compared to SE group, HSE had increased SE latency, reduced number of rats with SRS, reduced mossy fiber sprouting at 60days, and reduced cell death in the hilus and the CA3 region 1 and 60days after SE. Additionally, HSE rats had better spatial memory performance than SE rats. Our findings indicated that short hypoxic preconditioning preceding SE promotes long-lasting protective effects on neuron survival and spatial memory.

High-fat diet increases respiratory frequency and abdominal expiratory motor activity during hypercapnia

Breathing disorders are commonly observed in association with obesity. Here we tested whether high-fat diet (HFD) impairs the chemoreflex ventilatory response. Male Holtzman rats (300-320 g) were fed with standard chow diet (SD) or HFD for 12 weeks. Then, tidal volume (VT), respiratory frequency (fR) and pulmonary ventilation (VE) were determined in conscious rats during basal condition, hypercapnia (7% or 10% CO2) or hypoxia (7% O2). The mean arterial pressure (MAP), heart rate (HR) and baroreflex sensitivity were also evaluated in conscious rats. A group of anesthetized rats was used for the measurements of the activity of inspiratory (diaphragm) and expiratory (abdominal) muscles under the same gas conditions. Baseline fR, VT and VE were similar between SD and HFD rats. During hypercapnia, the increase of fR was exacerbated in conscious HFD rats (60 ± 3, vs. SD: 47 ± 3 Δ breaths.min-1, P < 0.05). In anesthetized rats, hypercapnia strongly increased abdominal muscle activity in HFD group (238 ± 27, vs. basal condition: 100 ± 0.3%; P < 0.05), without significant change in SD group (129 ± 2.1, vs. basal condition: 100 ± 0.8%; P = 0.34). The ventilatory responses to hypoxia were similar between groups. In conscious HFD rats, MAP and HR were elevated and the baroreflex function was impaired (P < 0.05). These data demonstrated that 12 weeks of HFD exaggerate the ventilatory response activated by hypercapnia. The mechanisms involved in these responses need more investigation in future studies.