Facilitation of breathing by leptin effects in the central nervous system.

With the global epidemic of obesity, breathing disorders associated with excess body weight have markedly increased. Respiratory dysfunctions caused by obesity were originally attributed to mechanical factors; however, recent studies have suggested a pathophysiological component that involves the central nervous system (CNS) and hormones such as leptin produced by adipocytes as well as other cells. Leptin is suggested to stimulate breathing and leptin deficiency causes an impairment of the chemoreflex, which can be reverted by leptin therapy. This facilitation of the chemoreflex may depend on the action of leptin in the hindbrain areas involved in the respiratory control such as the nucleus of the solitary tract (NTS), a site that receives chemosensory afferents, and the ventral surface of the medulla that includes the retrotrapezoid nucleus (RTN), a central chemosensitive area, and the rostral ventrolateral medulla (RVLM). Although the mechanisms and pathways activated by leptin to facilitate breathing are still not completely clear, evidence suggests that the facilitatory effects of leptin on breathing require the brain melanocortin system, including the POMC-MC4R pathway, a mechanism also activated by leptin to modulate blood pressure. The results of all the studies that have investigated the effect of leptin on breathing suggest that disruption of leptin signalling as caused by obesity-induced reduction of central leptin function (leptin resistance) is a relevant mechanism that may contribute to respiratory dysfunctions associated with obesity.

High sodium intake during postnatal phases induces an increase in arterial blood pressure in adult rats.

Epigenetic studies suggest that diseases that develop in adulthood are related to certain conditions to which the individual is exposed during the initial stages of life. Experimental evidence has demonstrated that offspring born to mothers maintained on high-Na diets during pregnancy have higher mean arterial pressure (MAP) in adulthood. Although these studies have demonstrated the importance of prenatal phases to hypertension development, no evidence regarding the role of high Na intake during postnatal phases in the development of this pathology has been reported. Therefore, in the present study, the effects of Na overload during childhood on induced water and Na intakes and on cardiovascular parameters in adulthood were evaluated. Experiments were carried out in two groups of 21-d-old rats: experimental group, maintained on hypertonic saline (0.3 m-NaCl) solution and food for 60 d, and control group, maintained on tap water and food. Later, both groups were given water and food for 15 d (recovery period). After the recovery period, chronic cannulation of the right femoral artery was performed in unanaesthetised rats to record baseline MAP and heart rate (HR). The experimental group was found to have increased basal MAP (98.6 (sem 2.6) v. 118.3 (sem 2.7) mmHg, P< 0.05) and HR (365.4 (sem 12.2) v. 398.2 (sem 7.5) beats per min, P< 0.05). There was a decrease in the baroreflex index in the experimental group when compared with that in the control group. A water and Na intake test was performed using furosemide. Na depletion was found to induce an increase in Na intake in both the control and experimental groups (12.1 (sem 0.6) ml and 7.8 (sem 1.1), respectively, P< 0.05); however, this increase was of lower magnitude in the experimental group. These results demonstrate that postnatal Na overload alters behavioural and cardiovascular regulation in adulthood.

Interaction of central angiotensin II and aldosterone on sodium intake and blood pressure.

Recent studies demonstrated an important natriorexigenic mechanism activated by aldosterone acting in the hindbrain. Studies have also shown that aldosterone effects are intensified by angiotensin II (ANG II) and vice-versa. Thus, the aim of the present work was to test if angiotensinergic mechanisms in the forebrain are involved on sodium appetite to aldosterone infused into the 4th V and also if aldosterone into the 4th V might facilitate ingestive and cardiovascular responses to central ANG II. Male Holtzman rats with stainless steel cannulas implanted into the 4th ventricle (4th V) and lateral ventricle (LV) had access to 1.8% NaCl during 2 h/day. Chronic infusion of aldosterone (100 ng/h) into the 4th V for 7 days strongly increased 1.8% NaCl intake (16.1 ±â€¯2.2 ml/2h/day). Losartan (AT1 receptor antagonist, 50 µg/1 µl) acutely injected into the LV reduced 1.8% NaCl intake induced by aldosterone infusion into the 4th V (8.8 ±â€¯2.3 ml/2h/day). The pressor response to ANG II (50 ng/1 µl) into the LV increased in rats treated with aldosterone into the 4th V (45 ±â€¯5 mmHg, vs. vehicle infusion: 26 ±â€¯4 mmHg). Similarly, fluid intake (water + 1.8% NaCl) also increased when rats receiving aldosterone infusion were treated with ANG II acutely into the LV. These results suggest that forebrain angiotensinergic mechanisms are important for sodium intake produced by aldosterone acting in the hindbrain. In addition, aldosterone in the hindbrain produces sensitization of the central pressor mechanisms activated by ANG II acting in the forebrain.

Aldosterone infusion into the 4th ventricle produces sodium appetite with baroreflex attenuation independent of renal or blood pressure changes.

Aldosterone infusion into the 4th ventricle (4th V), upstream the nucleus of the solitary tract (NTS), produces strong 0.3 M NaCl intake. In the present study, we investigated whether aldosterone infusion into the 4th V activates HSD2 neurons, changes renal excretion, or alters blood pressure and cardiovascular reflexes. Chronic infusion of aldosterone (100 ng/h) into the 4th V increased daily 0.3 M NaCl intake (up to 44 ±â€¯10, vs. vehicle: 5.6 ±â€¯3.4 ml/24 h) and also c-Fos expression in HSD2 neurons in the NTS and in non-HSD2 neurons in the NTS. Natriuresis, diuresis and positive sodium balance were present in rats that ingested 0.3 M NaCl, however, renal excretion was not modified by 4th V aldosterone in rats that had no access to NaCl. 4th V aldosterone also reduced baroreflex sensitivity (-2.8 ±â€¯0.5, vs. vehicle: -5.1 ±â€¯0.9 bpm/mmHg) in animals that had sodium available, without changing blood pressure. The results suggest that sodium intake induced by aldosterone infused into the 4th V is associated with activation of NTS neurons, among them the HSD2 neurons. Aldosterone infused into the 4th V in association with sodium intake also impairs baroreflex sensitivity, without changing arterial pressure.

Lesions of the commissural subnucleus of the nucleus of the solitary tract increase isoproterenol-induced water intake.

The nucleus of the solitary tract (NTS) is the primary site of the cardiovascular afferent information about arterial blood pressure and volume. The NTS projects to areas in the central nervous system involved in cardiovascular regulation and hydroelectrolyte balance, such as the anteroventral third ventricle region and the lateral parabrachial nucleus. The aim of the present study was to investigate the effects of electrolytic lesion of the commissural NTS on water and 0.3 M NaCl intake and the cardiovascular responses to subcutaneous injection of isoproterenol. Male Holtzman rats weighing 280 to 320 g were submitted to sham lesion or electrolytic lesion of the commissural NTS (N = 6-15/group). The sham-lesioned rats had the electrode placed along the same coordinates, except that no current was passed. Water intake induced by subcutaneous isoproterenol (30 microg/kg body weight) significantly increased in chronic (15 days) commissural NTS-lesioned rats (to 2.4 +/- 0.2 vs sham: 1.9 +/- 0.2 mL 100 g body weight-1 60 min-1). Isoproterenol did not induce any sodium intake in sham or in commissural NTS-lesioned rats. The isoproterenol-induced hypotension (sham: -27 +/- 4 vs commissural NTS-lesioned rats: -22 +/- 4 mmHg/20 min) and tachycardia (sham: 168 +/- 10 vs commissural NTS: 144 +/- 24 bpm/20 min) were not different between groups. The present results suggest that the commissural NTS is part of an inhibitory neural pathway involved in the control of water intake induced by subcutaneous isoproterenol, and that the overdrinking observed in lesioned rats is not the result of a cardiovascular imbalance in these animals.

Rapid stimulation of sodium intake combining aldosterone into the 4th ventricle and the blockade of the lateral parabrachial nucleus.

Chronic infusion of aldosterone into the 4th ventricle (4th V) induces robust daily sodium intake, whereas acute injection of aldosterone into the 4th V produces no sodium intake. The inhibitory mechanism of the lateral parabrachial nucleus (LPBN) restrains sodium intake induced by different natriorexigenic stimuli and might affect the acute response to aldosterone into the 4th V. In the present study, 1.8% NaCl and water intake was tested in rats treated with acute injections of aldosterone into the 4th V combined with the blockade of the inhibitory mechanisms with injections of moxonidine (α2 adrenergic/imidazoline agonist) or methysergide (a serotonergic antagonist) into the LPBN. Male Holtzman rats with stainless steel cannulas implanted in the 4th V and bilaterally in the LPBN were used. Aldosterone (250 or 500ng) into the 4th V combined with vehicle into the LPBN induced no 1.8% NaClintake compared to control (1.5±1.1 and 1.1±0.4, respectively, vs. vehicle into 4th V: 1.0±0.5ml/2h). However, aldosterone (250 or 500ng) into the 4th V combined with moxonidine (0.5nmol) into the LPBN induced strong ingestion of 1.8% NaCl (12.7±4.6 and 17.6±3.7ml/2h, respectively). Aldosterone (250ng) into the 4th V combined with methysergide (4µg) into the LPBN also induced 1.8% NaCl intake (17.6±5.4ml/2h). These data suggest that the inhibitory mechanisms of the LPBN counteract the facilitation of sodium intake produced by aldosterone injected into the 4th, restraining sodium intake in this condition.

Neuronal circuits involved in osmotic challenges.

The maintenance of plasma sodium concentration within a narrow limit is crucial to life. When it differs from normal physiological patterns, several mechanisms are activated in order to restore body fluid homeostasis. Such mechanisms may be vegetative and/or behavioral, and several regions of the central nervous system (CNS) are involved in their triggering. Some of these are responsible for sensory pathways that perceive a disturbance of the body fluid homeostasis and transmit information to other regions. These regions, in turn, initiate adequate adjustments in order to restore homeostasis. The main cardiovascular and autonomic responses to a change in plasma sodium concentration are: i) changes in arterial blood pressure and heart rate; ii) changes in sympathetic activity to the renal system in order to ensure adequate renal sodium excretion/absorption, and iii) the secretion of compounds involved in sodium ion homeostasis (ANP, Ang-II, and ADH, for example). Due to their cardiovascular effects, hypertonic saline solutions have been used to promote resuscitation in hemorrhagic patients, thereby increasing survival rates following trauma. In the present review, we expose and discuss the role of several CNS regions involved in body fluid homeostasis and the effects of acute and chronic hyperosmotic challenges.

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

AIM: 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. METHODS: Rats were exposed to AIH (10 × 6-7% O2 for 45 s, every 5 min), and the cardiorespiratory parameters were evaluated during 60 min using in vivo and in situ approaches. RESULTS: In unanesthetized conditions (n = 9), AIH elicited a modest but sustained increase in baseline mean arterial pressure (MAP, 104 ± 2 vs. 111 ± 3 mmHg, P < 0.05) associated with enhanced sympathetic and respiratory-related variabilities. In the in situ preparations (n = 9), AIH evoked LTF in phrenic (33 ± 12%), thoracic sympathetic (75 ± 25%) and abdominal nerve activities (69 ± 14%). The sympathetic overactivity after AIH was phase-locked with the emergence of bursts in abdominal activity during the late-expiratory phase. In anesthetized vagus-intact animals, AIH increased baseline MAP (113 ± 3 vs. 122 ± 2 mmHg, P < 0.05) and abdominal muscle activity (535 ± 94%), which were eliminated after pharmacological inhibition of the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG). CONCLUSION: These findings indicate that increased expiratory activity is also an important component of AIH-elicited respiratory LTF. Moreover, the development of sympathetic LTF after AIH is linked to the emergence of active expiratory pattern and depends on the integrity of the neurones of the RTN/pFRG.

The bradycardic and hypotensive responses to serotonin are reduced by activation of GABAA receptors in the nucleus tractus solitarius of awake rats.

We investigated the effects of bilateral injections of the GABA receptor agonists muscimol (GABA A) and baclofen (GABA B) into the nucleus tractus solitarius (NTS) on the bradycardia and hypotension induced by iv serotonin injections (5-HT, 2 microg/rat) in awake male Holtzman rats. 5-HT was injected in rats with stainless steel cannulas implanted bilaterally in the NTS, before and 5, 15, and 60 min after bilateral injections of muscimol or baclofen into the NTS. The responses to 5-HT were tested before and after the injection of atropine methyl bromide. Muscimol (50 pmol/50 nl, N = 8) into the NTS increased basal mean arterial pressure (MAP) from 115 +/- 4 to 144 +/- 6 mmHg, did not change basal heart rate (HR) and reduced the bradycardia (-40 +/- 14 and -73 +/- 26 bpm at 5 and 15 min, respectively, vs -180 +/- 20 bpm for the control) and hypotension (-11 +/- 4 and -14 +/- 4 mmHg, vs -40 +/- 9 mmHg for the control) elicited by 5-HT. Baclofen (12.5 pmol/50 nl, N = 7) into the NTS also increased basal MAP, but did not change basal HR, bradycardia or hypotension in response to 5-HT injections. Atropine methyl bromide (1 mg/kg body weight) injected iv reduced the bradycardic and hypotensive responses to 5-HT injections. The stimulation of GABA A receptors in the NTS of awake rats elicits a significant increase in basal MAP and decreases the cardiac Bezold-Jarisch reflex responses to iv 5-HT injections.

Baroreflex function in conscious rats submitted to iron overload.

Our hypothesis is that iron accumulated in tissue, rather than in serum, may compromise cardiovascular control. Male Fischer 344 rats weighing 180 to 220 g were divided into 2 groups. In the serum iron overload group (SIO, N = 12), 20 mg elemental iron was injected ip daily for 7 days. In the tissue iron overload group (TIO, N = 19), a smaller amount of elemental iron was injected (10 mg, daily) for 5 days followed by a resting period of 7 days. Reflex heart rate responses were elicited by iv injections of either phenylephrine (0.5 to 5.0 microg/kg) or sodium nitroprusside (1.0 to 10.0 microg/kg). Baroreflex curves were determined and fitted to sigmoidal equations and the baroreflex gain coefficient was evaluated. To evaluate the role of other than a direct effect of iron on tissue, acute treatment with the iron chelator deferoxamine (20 mg/kg, iv) was performed on the TIO group and the baroreflex was re-evaluated. At the end of the experiments, evaluation of iron levels in serum confirmed a pronounced overload for the SIO group (30-fold), in contrast to the TIO group (2-fold). Tissue levels of iron, however, were higher in the TIO group. The SIO protocol did not produce significant alterations in the baroreflex curve response, while the TIO protocol produced a nearly 2-fold increase in baroreflex gain (-4.34 +/- 0.74 and -7.93 +/- 1.08 bpm/mmHg, respectively). The TIO protocol animals treated with deferoxamine returned to sham levels of baroreflex gain (-3.7 +/- 0.3 sham vs -3.6 +/- 0.2 bpm/mmHg) 30 min after the injection. Our results indicate an effect of tissue iron overload on the enhancement of baroreflex sensitivity.

Hydrogen peroxide attenuates the dipsogenic, renal and pressor responses induced by cholinergic activation of the medial septal area.

Cholinergic activation of the medial septal area (MSA) with carbachol produces thirst, natriuresis, antidiuresis and pressor response. In the brain, hydrogen peroxide (H2O2) modulates autonomic and behavioral responses. In the present study, we investigated the effects of the combination of carbachol and H2O2 injected into the MSA on water intake, renal excretion, cardiovascular responses and the activity of vasopressinergic and oxytocinergic neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Furthermore, the possible modulation of carbachol responses by H2O2 acting through K+ATP channels was also investigated. Male Holtzman rats (280-320 g) with stainless steel cannulas implanted in the MSA were used. The pre-treatment with H2O2 in the MSA reduced carbachol-induced thirst (7.9±1.0, vs. carbachol: 13.2±2.0 ml/60 min), antidiuresis (9.6±0.5, vs. carbachol: 7.0±0.8 ml/120 min,), natriuresis (385±36, vs. carbachol: 528±46 µEq/120 min) and pressor response (33±5, vs. carbachol: 47±3 mmHg). Combining H2O2 and carbachol into the MSA also reduced the number of vasopressinergic neurons expressing c-Fos in the PVN (46.4±11.2, vs. carbachol: 98.5±5.9 c-Fos/AVP cells) and oxytocinergic neurons expressing c-Fos in the PVN (38.5±16.1, vs. carbachol: 75.1±8.5 c-Fos/OT cells) and in the SON (57.8±10.2, vs. carbachol: 102.7±7.4 c-Fos/OT cells). Glibenclamide (K+ATP channel blocker) into the MSA partially reversed H2O2 inhibitory responses. These results suggest that H2O2 acting through K+ATP channels in the MSA attenuates responses induced by cholinergic activation in the same area.

Sodium intake combining cholinergic activation and noradrenaline into the lateral parabrachial nucleus.

The administration of cholinergic agonists like pilocarpine intraperitoneally (i.p.) or carbachol intracerebroventricularly (i.c.v.) induces water, but non significant hypertonic NaCl intake. These treatments also produce pressor responses, which may inhibit sodium intake. Noradrenaline (NOR) acting on α2-adrenoceptors in the lateral parabrachial nucleus (LPBN) deactivates inhibitory mechanisms increasing fluid depletion-induced sodium intake. In the present study, we investigated: (1) water and 1.8% NaCl intake in rats treated with pilocarpine i.p. or carbachol i.c.v. combined with NOR into the LPBN; (2) if inhibitory signals from cardiovascular receptors are blocked by NOR in the LPBN. Male Holtzman rats with stainless steel guide-cannulas implanted in the lateral ventricle and bilaterally in the LPBN were used. Bilateral injections of NOR (80nmol/0.2µl) into the LPBN decreased water intake (0.8±0.3, vs. saline (SAL): 2.9±0.3ml/180min) induced by pilocarpine (1mg/kg of body weight) i.p., without changing 1.8% NaCl intake (0.8±2.4, vs. SAL: 0.5±0.3ml/180min). Prazosin (1mg/kg of body weight) i.p. blocked pressor responses and increased water and 1.8% NaCl intake (6.3±1.7 and 14.7±3.5ml/180min, respectively) in rats treated with pilocarpine combined with NOR into the LPBN. Prazosin i.p. also increased 1.8% NaCl intake in rats treated with carbachol i.c.v combined with NOR into the LPBN. The results suggest that different signals inhibit sodium intake in rats treated with cholinergic agonists, among them those produced by increases of arterial pressure that are not efficiently deactivated by NOR acting in the LPBN.

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.

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

UNLABELLED: 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 neurones (LepR/POMC-cre) and in MC4R knockout (MC4R(-/-) ) and wild-type mice. RESULTS: Leptin (5 µg day(-1) ) reduced body weight (~17%) and increased ventilatory response to hypercapnia, whereas SHU9119 (0.6 nmol day(-1) ) increased body weight (~18%) and reduced ventilatory responses compared with control-PBS group (Lep: 2119 ± 90 mL min(-1)  kg(-1) and 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 hypercapnia (1391 ± 137 mL min(-1)  kg(-1) ). The ventilatory response to hypercapnia 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.

Commissural NTS lesions and cardiovascular responses in aortic baroreceptor-denervated rats.

Both acute (1 day) lesions of the commissural nucleus of the solitary tract (commNTS) and aortic baroreceptor denervation increase pressor responses to bilateral common carotid occlusion (BCO) during a 60-second period in conscious rats. In this study, we investigated the following: (1) the effects of commNTS lesions on basal mean arterial pressure (MAP) and heart rate (HR) of aortic denervated (ADNx) rats; (2) the effects of acute commNTS lesions on pressor responses to BCO in ADNx rats; and (3) the effects of chronic (10 days) commNTS lesions on the pressor response to BCO. ADNx increased basal MAP and HR in sham-lesioned rats. Acute commNTS lesions abolished the MAP and HR increases observed in ADNx rats. Acute commNTS lesions increased the pressor responses to BCO in rats with intact-baroreceptor innervation but produced no additional change in the pressor response to BCO in ADNx rats. Chronic commNTS lesions did not change the pressor responses to BCO in rats with intact-baroreceptor innervation. The data show that acute commNTS lesions abolish the MAP increase produced by aortic baroreceptor denervation. They also suggest that acute commNTS lesions enhance the pressor response to BCO by partial withdrawal of aortic baroreceptor inputs into the NTS. Chronically, reorganization in the remaining aortic baroreceptor or in the baroreflex function as a whole might produce normalization of the cardiovascular responses to BCO.

Role of endogenous carbon monoxide in central regulation of arterial pressure.

We investigated the contribution of neural mechanisms to the arterial pressure increase produced by zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG), an inhibitor of endogenous carbon monoxide synthesis. The arterial baroreceptor reflex control of heart rate was examined in rats with and without ZnDPBG pretreatment (45 micromol/kg IP) by analysis of the arterial pressure-heart rate relationship during infusions of phenylephrine or sodium nitroprusside to vary arterial pressure. ZnDPBG increased arterial pressure from 110 +/- 3 to 126 +/- 2 mm Hg without eliciting bradycardia. The maximum gain of the heart rate response to changes in arterial pressure was attenuated by ZnDPBG treatment (-1.9 +/- 0.3 versus -4.8 +/- 1.0 bpm/mm Hg). The possibility that ZnDPBG elevates arterial pressure by attenuating baroreceptor reflex function was addressed by comparing the pressor response to ZnDPBG (45 micromol/kg IP) in rats with and without sinoaortic denervation. The pressor effect of ZnDPBG was similar in rats with and without arterial baroreceptor deafferentation, implying that the increase in pressure is not simply the consequence of attenuated baroreceptor reflex function per se. The possibility that ZnDPBG increases arterial pressure via an effect on the nucleus tractus solitarii (NTS) also was investigated. ZnDPBG (1 nmol in 100 nL) injected into the NTS of rats increased arterial pressure from 111 +/- 4 to 126 +/- 5 mm Hg, and this effect was reversed by an ipsilateral microinjection of carbon monoxide into the NTS. Accordingly, the pressor effect of ZnDPBG may rely on inhibition of carbon monoxide production in the NTS. This implies that carbon monoxide formed by brain heme oxygenase plays a role in the central regulation of arterial pressure.

Denervation supersensitivity to glutamate in the nucleus tractus solitarii after removal of the nodose ganglion.

If L-glutamate (L-Glu) is the transmitter released from cardiovascular vagal afferent nerve fibers in the nucleus tractus solitarii (NTS), then interruption of those afferents should lead to denervation supersensitivity to L-Glu in the NTS. Therefore, we sought to determine if dose-related changes in arterial pressure (AP) and heart rate (HR) elicited by L-Glu microinjected into the NTS evolve after removal of the left nodose ganglion in rats. Twelve rats served as unoperated controls; and eight were studied 5 days, eleven 10 days, and nine 15 days after ganglionectomy. Each rat was anesthetized with halothane (1.5-2.0%) and cannulated for recording AP and HR. After exposure of the brainstem, vehicle or L-Glu (3, 30, 75, 150, 300 and 1500 pmol/50 nl) was microinjected alternately into the right and left dorsomedial NTS. In control animals, and in animals 5 days and 15 days after ganglionectomy, the lowest dose of L-Glu that produced a significant fall of mean AP (-10 +/- 2, -5 +/- 2, -6 +/- 1 mmHg, respectively) was 30 pmoles. The threshold dose with injections on the lesioned side 10 days after ganglionectomy was 3 pmol (-8 +/- 2 mmHg). In rats studied at 10 days, but not in control, 5 or 15 days rats, the dose-responses for injections made on the left were shifted significantly to the left of those made on the right (P < 0.05). In control, 5, and 15 day rats there were no significant differences between dose-related responses elicited from right and left NTS.(ABSTRACT TRUNCATED AT 250 WORDS)

NMDA receptor antagonist blocks the bradycardic but not the pressor response to L-glutamate microinjected into the nucleus tractus solitarius (NTS) of unanesthetized rats.

In the present study we evaluated the role of NMDA receptors on the pressor and bradycardic responses to L-glutamate (L-Glu) microinjected into the nucleus tractus solitarius (NTS) of unanesthetized rats. L-Glu (1 nmol/100 nl) was microinjected into the NTS before and 10 min after microinjection of phosponovaleric acid (AP-5), a selective NMDA receptor antagonist, into the NTS of three different groups of rats (0.5, 2.0 and 10.0 nmol/100 nl). Microinjection of AP-5 into the NTS produced a dose-dependent reduction in the bradycardic response to L-Glu. However, no significant change in the pressor response to L-Glu was observed. These results indicate that the activation of the cardiovagal component (bradycardia) by L-Glu involves NMDA receptors and suggest that the activation of the sympatho-excitatory component (pressor response) by L-Glu in the commissural NTS is mediated by non-NMDA receptors.

Commissural nucleus of the solitary tract lesions reduce food intake and body weight gain in rats.

This study investigated the effects of an electrolytic lesion of the commissural subnucleus of the nucleus of the solitary tract (commNTS) on body weight, daily food and water intake, and plasma glucose and insulin in rats. In the first 6 days following brain surgery, commNTS lesioned rats reduced daily food intake by 80% compared to rats with sham lesions. After this period rats with lesions of commNTS started recovering food intake, but intake remained significantly reduced until the 12th day after surgery. A reduction in body weight was observed 4 days after surgery and reached a maximum on the 12th day. After this, a partial recovery of body weight was observed, but weight remained significantly reduced compared to weights of rats with sham lesions through the conclusion of the study. Food intake and body weight gain in other rats with partial lesions of the commNTS or with lesions outside the commNTS did not differ from rats with sham lesions with regard to those variables. Daily water intake and plasma glucose and insulin were not changed by the commNTS lesions. These results suggest that commNTS is involved with mechanisms that control food intake and body weight in rats.

Role of carbon monoxide in L-glutamate-induced cardiovascular responses in nucleus tractus solitarius of conscious rats.

Heme oxygenase degrades heme to form carbon monoxide. It has been reported that heme oxygenase-derived carbon monoxide may interact with L-glutamate (L-Glu) receptors in the nucleus tractus solitarius (NTS). Integrative studies suggest that heme oxygenase inhibitors raise blood pressure, in part, by inhibiting carbon monoxide formation in the NTS. The currents studies were designed to determine if heme oxygenase inhibitors affect the cardiovascular actions of L-Glu in the NTS. Accordingly, MAP and HR responses to unilateral microinjections of L-Glu (5 nmol/100 nl) into the NTS were measured before and after ipsilateral microinjections of zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG, 4.5 nmol/100 nl) or chromium mesoporphyrin (CrMP, 1.5 nmol/100 nl) in awake rats chronically instrumented with NTS guide cannulaes and arterial catheters. With respect to non-treatment (+36+/-5 mmHg, -107 bpm, n=10), ZnDPBG pre-treatment attenuated the pressor and bradycardic responses to L-Glu (+7+/-3 mmHg, -10+/-6 bpm, P<0.05). CrMP similarly attenuated cardiovascular responses to L-Glu (+47+/-3 mmHg, -68+/-8 bpm vs. +20+/-5 mmHg, -40+/-9 bpm; before vs. after, n=10, P<0.05). Matched series yielded no vehicle- or time-related effects. Our findings suggest that a heme oxygenase product, such as carbon monoxide, may affect NTS glutamatergic neurotransmission to participate in cardiovascular control.