RESUMEN
Renal denervation (RDN) is a potential therapy for drug-resistant hypertension. However, whether its effects are mediated by ablation of efferent or afferent renal nerves is not clear. Previous studies have implicated that renal inflammation and the sympathetic nervous system are driven by the activation of afferent and efferent renal nerves. RDN attenuated the renal inflammation and sympathetic activity in some animal models of hypertension. In the 2 kidney,1 clip (2K1C) model of renovascular hypertension, RDN also decreased sympathetic activity; however, mechanisms underlying renal and central inflammation are still unclear. We tested the hypothesis that the mechanisms by which total RDN (TRDN; efferent + afferent) and afferent-specific RDN (ARDN) reduce arterial pressure in 2K1C rats are the same. Male Sprague-Dawley rats were instrumented with telemeters to measure mean arterial pressure (MAP), and after 7 days, a clip was placed on the left renal artery. Rats underwent TRDN, ARDN, or sham surgery of the clipped kidney and MAP was measured for 6 wk. Weekly measurements of water intake (WI), urine output (UO), and urinary copeptin were conducted, and urine was analyzed for cytokines/chemokines. Neurogenic pressor activity (NPA) was assessed at the end of the protocol calculated by the depressor response after intraperitoneal injection of hexamethonium. Rats were euthanized and the hypothalamus and kidneys removed for measurement of cytokine content. MAP, NPA, WI, and urinary copeptin were significantly increased in 2K1C-sham rats, and these responses were abolished by both TRDN and ARDN. 2K1C-sham rats presented with renal and hypothalamic inflammation and these responses were largely mitigated by TRDN and ARDN. We conclude that RDN attenuates 2K1C hypertension primarily by ablation of afferent renal nerves which disrupts bidirectional renal neural-immune pathways.NEW & NOTEWORTHY Hypertension resulting from reduced perfusion of the kidney is dependent on renal sensory nerves, which are linked to inflammation in the kidney and hypothalamus. Afferent renal nerves are required for chronic increases in both water intake and vasopressin release observed following renal artery stenosis. Findings from this study suggest an important role of renal sensory nerves that has previously been underestimated in the pathogenesis of 2K1C hypertension.
Asunto(s)
Hipertensión Renovascular , Hipertensión , Nefritis , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Riñón , Sistema Nervioso Simpático , Hipotálamo , Inflamación , Presión Sanguínea/fisiologíaRESUMEN
Recent evidence has suggested that the carotid bodies might act as immunological sensors, detecting pro-inflammatory mediators and signalling to the central nervous system, which, in turn, orchestrates autonomic responses. Here, we confirmed that the TNF-α receptor type I is expressed in the carotid bodies of rats. The systemic administration of TNF-α increased carotid body afferent discharge and activated glutamatergic neurons in the nucleus tractus solitarius (NTS) that project to the rostral ventrolateral medulla (RVLM), where many pre-sympathetic neurons reside. The activation of these neurons was accompanied by an increase in splanchnic sympathetic nerve activity. Carotid body ablation blunted the TNF-α-induced activation of RVLM-projecting NTS neurons and the increase in splanchnic sympathetic nerve activity. Finally, plasma and spleen levels of cytokines after TNF-α administration were higher in rats subjected to either carotid body ablation or splanchnic sympathetic denervation. Collectively, our findings indicate that the carotid body detects circulating TNF-α to activate a counteracting sympathetic anti-inflammatory mechanism.
Asunto(s)
Cuerpo Carotídeo , Animales , Antiinflamatorios , Bulbo Raquídeo/fisiología , Ratas , Ratas Sprague-Dawley , Reflejo , Núcleo Solitario/fisiología , Sistema Nervioso Simpático/fisiología , Factor de Necrosis Tumoral alfaRESUMEN
The nucleus of the solitary tract (NTS) is an important area of the brainstem that receives and integrates afferent cardiorespiratory sensorial information, including those from arterial chemoreceptors and baroreceptors. It was described that acetylcholine (ACh) in the commissural subnucleus of the NTS (cNTS) promotes an increase in the phrenic nerve activity (PNA) and antagonism of nicotinic receptors in the same region reduces the magnitude of tachypneic response to peripheral chemoreceptor stimulation, suggesting a functional role of cholinergic transmission within the cNTS in the chemosensory control of respiratory activity. In the present study, we investigated whether cholinergic receptor antagonism in the cNTS modifies the sympathetic and respiratory reflex responses to hypercapnia. Using an arterially perfused in situ preparation of juvenile male Holtzman rats, we found that the nicotinic antagonist (mecamylamine, 5 mM), but not the muscarinic antagonist (atropine, 5 mM), into the cNTS attenuated the hypercapnia-induced increase of hypoglossal activity. Furthermore, mecamylamine in the cNTS potentiated the generation of late-expiratory (late-E) activity in abdominal nerve induced by hypercapnia. None of the cholinergic antagonists microinjected in the cNTS changed either the sympathetic or the phrenic nerve responses to hypercapnia. Our data provide evidence for the role of cholinergic transmission in the cNTS, acting on nicotinic receptors, modulating the hypoglossal and abdominal responses to hypercapnia.
Asunto(s)
Neuronas Colinérgicas/fisiología , Hipercapnia/metabolismo , Respiración , Transmisión Sináptica , Comisuras Telencefálicas/fisiología , Animales , Atropina/farmacología , Neuronas Colinérgicas/efectos de los fármacos , Hipercapnia/fisiopatología , Nervio Hipogloso/fisiología , Masculino , Mecamilamina/farmacología , Agonistas Muscarínicos/farmacología , Antagonistas Nicotínicos/farmacología , Nervio Frénico/fisiología , Ratas , Receptores Colinérgicos/metabolismo , Reflejo , Núcleo Solitario/fisiología , Núcleo Solitario/fisiopatología , Comisuras Telencefálicas/fisiopatologíaRESUMEN
The two kidney-one clip (2K1C) renovascular hypertension depends on the renin-angiotensin system and sympathetic overactivity. The maintenance of 2K1C hypertension also depends on inputs from the carotid bodies (CB), which when activated stimulate the respiratory activity. In the present study, we investigated the importance of CB afferent activity for the ventilatory responses in 2K1C hypertensive rats and for phrenic and hypoglossal activities in in situ preparations of normotensive rats treated with angiotensin II. Silver clips were implanted around the left renal artery of male Holtzman rats (150 g) to induce renovascular hypertension. Six weeks after clipping, hypertensive 2K1C rats showed, in conscious state, elevated resting tidal volume and minute ventilation compared with the normotensive group. 2K1C rats also presented arterial alkalosis, urinary acidification, and amplified hypoxic ventilatory response. Carotid body removal (CBR), 2 wk before the experiments (4th week after clipping), significantly reduced arterial pressure and pulmonary ventilation in 2K1C rats but not in normotensive rats. Intra-arterial administration of angiotensin II in the in situ preparation of normotensive rats increased phrenic and hypoglossal activities, responses that were also reduced after CBR. Results show that renovascular hypertensive rats exhibit increased resting ventilation that depends on CB inputs. Similarly, angiotensin II increases phrenic and hypoglossal activities in in situ preparations of normotensive rats, responses that also depend on CB inputs. Results suggest that mechanisms that depend on CB inputs in renovascular hypertensive rats or during angiotensin II administration in normotensive animals increase respiratory drive.
Asunto(s)
Cuerpo Carotídeo/fisiología , Hipertensión Renovascular/fisiopatología , Ratas Sprague-Dawley , Angiotensina II/administración & dosificación , Angiotensina II/farmacología , Animales , Nervio Hipogloso/fisiología , Masculino , Fenilefrina/administración & dosificación , Fenilefrina/farmacología , Nervio Frénico/fisiología , Ratas , Sistema Nervioso Simpático , Simpatomiméticos/farmacologíaRESUMEN
Sickness behaviour, a syndrome characterized by a general reduction in animal activity, is part of the active-phase response to fight infection. Lipopolysaccharide (LPS), an effective endotoxin to model sickness behaviour, reduces thirst and sodium excretion, and increases neurohypophysial secretion. Here we review the effects of LPS on thirst and sodium appetite. Altered renal function and hydromineral fluid intake in response to LPS occur in the context of behavioural reorganization, which manifests itself as part of the syndrome. Recent data show that, in addition to its classical effect on thirst, non-septic doses of LPS injected intraperitoneally produce a preferential inhibition of intracellular thirst versus extracellular thirst. Moreover, LPS also reduced hypertonic NaCl intake in sodium-depleted rats that entered a sodium appetite test. Antagonism of α2 -adrenoceptors abolished the effect of LPS on sodium appetite. LPS and cytokine transduction potentially recruit brain noradrenaline and α2 -adrenoceptors to control sodium appetite and sickness behaviour.
Asunto(s)
Apetito , Conducta de Enfermedad , Receptores Adrenérgicos alfa 2/metabolismo , Sodio/metabolismo , Animales , Lipopolisacáridos/toxicidad , Equilibrio HidroelectrolíticoRESUMEN
iSodium intake occurs either as a spontaneous or induced behavior, which is enhanced, i.e., sensitized, by repeated episodes of water deprivation followed by subsequent partial rehydration (WD-PR). In the present work, we examined whether repeated WD-PR alters hypothalamic transcripts related to the brain renin-angiotensin system (RAS) and apelin system in male normotensive Holtzman rats (HTZ). We also examined whether the sodium intake of a strain with genetically inherited high expression of the brain RAS, the spontaneously hypertensive rat (SHR), responds differently than HTZ to repeated WD-PR. We found that repeated WD-PR, besides enhancing spontaneous and induced 0.3 M NaCl intake, increased the hypothalamic expression of angiotensinogen, aminopeptidase N, and apelin receptor transcripts (43%, 60%, and 159%, respectively) in HTZ at the end of the third WD-PR. Repeated WD-PR did not change the daily spontaneous 0.3 M NaCl intake and barely changed the need-induced 0.3 M NaCl intake of SHR. The same treatment consistently enhanced spontaneous daily 0.3 M NaCl intake in the normotensive Wistar-Kyoto rats. The results show that repeated WD-PR produces alterations in hypothalamic transcripts and also sensitizes sodium appetite in HTZ. They suggest an association between the components of hypothalamic RAS and the apelin system, with neural and behavioral plasticity produced by repeated episodes of WD-PR in a normotensive strain. The results also indicate that the inherited hyperactive brain RAS is not a guarantee for sensitization of sodium intake in the male adult SHR exposed to repeated WD-PR.
Asunto(s)
Regulación del Apetito , Conducta Animal , Fluidoterapia , Hipertensión/metabolismo , Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , ARN Mensajero/metabolismo , Sistema Renina-Angiotensina , Cloruro de Sodio Dietético/administración & dosificación , Privación de Agua , Animales , Apelina , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Hipertensión/genética , Hipertensión/fisiopatología , Hipertensión/psicología , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Plasticidad Neuronal , ARN Mensajero/genética , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Sistema Renina-Angiotensina/genética , Factores de TiempoRESUMEN
History of sodium depletion cross-sensitizes the effects of drugs of abuse. The objective of the present study was to find out if history of sodium depletion also cross-sensitizes a natural reward such as sugar intake in the rat. Sodium depletion was induced by furosemide combined with removal of ambient sodium for 24 h; it was repeated seven days later. The depletion was immediately followed by 0.3 M NaCl intake in a sodium appetite test (active sodium repletion). Seven days after the last depletion, hydrated and fed (need-free) sucrose-naïve animals were offered 10% sucrose in a first 2-h sucrose test. The sucrose test was repeated once a day in a series of five consecutive days. History of sodium depletion enhanced sucrose intake in the first and second tests; it had no effect from the third to fifth sucrose test. The effect on the initial sucrose intake tests disappeared if the rats did not ingest 0.3 M NaCl in the sodium appetite test. Prior experience with sucrose intake in need-free conditions had no effect on sodium appetite. History of intracellular dehydration transiently influenced sucrose intake in the first sucrose test. We found no evidence for thirst sensitization. We conclude that history of dehydration, particularly that resulting from sodium depletion, combined to active sodium repletion, produced short-term cross-sensitization of sucrose intake in sucrose-naïve rats. The results suggest that the cross-sensitization of sucrose intake related with acquisition of sugar as a novel nutrient rather than production of lasting effects on sugar rewarding properties.
Asunto(s)
Dieta Hiposódica , Azúcares de la Dieta/administración & dosificación , Cloruro de Sodio Dietético/administración & dosificación , Sodio en la Dieta/administración & dosificación , Animales , Apetito , Deshidratación , Furosemida/administración & dosificación , Masculino , Ratas , Ratas Sprague-Dawley , SedRESUMEN
Noradrenergic A2 neurons of the nucleus of the solitary tract (NTS) have been suggested to contribute to body fluid homeostasis and cardiovascular regulation. In the present study, we investigated the effects of lesions of A2 neurons of the commissural NTS (cNTS) on the c-Fos expression in neurons of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, arterial pressure, water intake, and urinary excretion in rats with plasma hyperosmolality produced by intragastric 2 M NaCl (2 ml/rat). Male Holtzman rats (280-320 g) received an injection of anti-dopamine-ß-hydroxylase-saporin (12.6 ng/60 nl; cNTS/A2-lesion, n = 28) or immunoglobulin G (IgG)-saporin (12.6 ng/60 nl; sham, n = 24) into the cNTS. The cNTS/A2 lesions increased the number of neurons expressing c-Fos in the magnocellular PVN in rats treated with hypertonic NaCl (90 ± 13, vs. sham: 47 ± 20; n = 4), without changing the number of neurons expressing c-Fos in the parvocellular PVN or in the SON. Contrary to sham rats, intragastric 2 M NaCl also increased arterial pressure in cNTS/A2-lesioned rats (16 ± 3, vs. sham: 2 ± 2 mmHg 60 min after the intragastric load; n = 9), an effect blocked by the pretreatment with the vasopressin antagonist Manning compound (0 ± 3 mmHg; n = 10). In addition, cNTS/A2 lesions enhanced hyperosmolality-induced water intake (10.5 ± 1.4, vs. sham: 7.7 ± 0.8 ml/60 min; n = 8-10), without changing renal responses to hyperosmolality. The results suggest that inhibitory mechanisms dependent on cNTS/A2 neurons reduce water intake and vasopressin-dependent pressor response to an acute increase in plasma osmolality.
Asunto(s)
Neuronas Adrenérgicas/fisiología , Presión Sanguínea/fisiología , Agua Corporal/metabolismo , Núcleo Solitario/fisiología , Vasopresinas/metabolismo , Equilibrio Hidroelectrolítico/fisiología , Neuronas Adrenérgicas/citología , Animales , Regulación del Apetito/fisiología , Masculino , Acoplamiento Neurovascular/fisiología , Concentración Osmolar , Osmorregulación/fisiología , Ratas , Ratas Sprague-Dawley , Núcleo Solitario/citología , Vasoconstricción/fisiología , Desequilibrio HidroelectrolíticoRESUMEN
In states of sodium deficiency many animals seek and consume salty solutions to restore body fluid homeostasis. These behaviors reflect the presence of sodium appetite that is a manifestation of a pattern of central nervous system (CNS) activity with facilitatory and inhibitory components that are affected by several neurohumoral factors. The primary focus of this review is on one structure in this central system, the lateral parabrachial nucleus (LPBN). However, before turning to a more detailed discussion of the LPBN, a brief overview of body fluid balance-related body-to-brain signaling and the identification of the primary CNS structures and humoral factors involved in the control of sodium appetite is necessary. Angiotensin II, mineralocorticoids, and extracellular osmotic changes act on forebrain areas to facilitate sodium appetite and thirst. In the hindbrain, the LPBN functions as a key integrative node with an ascending output that exerts inhibitory influences on forebrain regions. A nonspecific or general deactivation of LPBN-associated inhibition by GABA or opioid agonists produces NaCl intake in euhydrated rats without any other treatment. Selective LPBN manipulation of other neurotransmitter systems [e.g., serotonin, cholecystokinin (CCK), corticotrophin-releasing factor (CRF), glutamate, ATP, or norepinephrine] greatly enhances NaCl intake when accompanied by additional treatments that induce either thirst or sodium appetite. The LPBN interacts with key forebrain areas that include the subfornical organ and central amygdala to determine sodium intake. To summarize, a model of LPBN inhibitory actions on forebrain facilitatory components for the control of sodium appetite is presented in this review.
Asunto(s)
Apetito/fisiología , Rombencéfalo/fisiología , Sodio en la Dieta , Animales , Inhibición Neural , Vías Nerviosas/fisiología , Prosencéfalo/fisiología , Equilibrio HidroelectrolíticoRESUMEN
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.
Asunto(s)
Acetilcolina/farmacología , Nervio Frénico/fisiología , Núcleo Solitario/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Animales , Atropina/farmacología , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Masculino , Mecamilamina/farmacología , Antagonistas Nicotínicos/farmacología , Ratas , Receptores Muscarínicos/efectos de los fármacos , Receptores Muscarínicos/fisiología , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/fisiologíaRESUMEN
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.
Asunto(s)
Apetito/fisiología , Ingestión de Alimentos/fisiología , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Mineralocorticoides/metabolismo , Rombencéfalo/fisiología , Sodio en la Dieta/metabolismo , Animales , Apetito/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Rombencéfalo/efectos de los fármacosRESUMEN
The nucleus of the solitary tract (NTS) is the primary site of visceral afferents to the central nervous system. In the present study, we investigated the effects of lesions in the commissural portion of the NTS (commNTS) on the activity of vasopressinergic neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, plasma vasopressin, arterial pressure, water intake, and sodium excretion in rats with plasma hyperosmolality produced by intragastric 2 M NaCl (2 ml/rat). Male Holtzman rats with 15-20 days of sham or electrolytic lesion (1 mA; 10 s) of the commNTS were used. CommNTS lesions enhanced a 2 M NaCl intragastrically induced increase in the number of vasopressinergic neurons expressing c-Fos in the PVN (28 ± 1, vs. sham: 22 ± 2 c-Fos/AVP cells) and SON (26 ± 4, vs. sham: 11 ± 1 c-Fos/AVP cells), plasma vasopressin levels (21 ± 8, vs. sham: 6.6 ± 1.3 pg/ml), pressor responses (25 ± 7 mmHg, vs. sham: 7 ± 2 mmHg), water intake (17.5 ± 0.8, vs. sham: 11.2 ± 1.8 ml/2 h), and natriuresis (4.9 ± 0.8, vs. sham: 1.4 ± 0.3 meq/1 h). The pretreatment with vasopressin antagonist abolished the pressor response to intragastric 2 M NaCl in commNTS-lesioned rats (8 ± 2.4 mmHg at 10 min), suggesting that this response is dependent on vasopressin secretion. The results suggest that inhibitory mechanisms dependent on commNTS act to limit or counterbalance behavioral, hormonal, cardiovascular, and renal responses to an acute increase in plasma osmolality.
Asunto(s)
Presión Sanguínea/fisiología , Ingestión de Líquidos/fisiología , Riñón/fisiología , Núcleo Solitario/metabolismo , Desequilibrio Hidroelectrolítico/metabolismo , Animales , Masculino , Concentración Osmolar , Oxitocina , Núcleo Hipotalámico Paraventricular/citología , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Núcleo Supraóptico/citología , VasopresinasRESUMEN
The retrotrapezoid nucleus (RTN), located in the parafacial region, contains glutamatergic neurons that express the transcriptor factor Phox2b and that are suggested to be central respiratory chemoreceptors. Studies in anaesthetized animals or in vitro have suggested that RTN neurons are important in the control of breathing by influencing respiratory rate, inspiratory amplitude and active expiration. However, the contribution of these neurons to cardiorespiratory control in conscious rats is not clear. Male Holtzman rats (280-300 g, n = 6-8) with bilateral stainless-steel cannulae implanted into the RTN were used. In conscious rats, the microinjection of the ionotropic glutamatergic agonist NMDA (5 pmol in 50 nl) into the RTN increased respiratory frequency (by 42%), tidal volume (by 21%), ventilation (by 68%), peak expiratory flow (by 24%) and mean arterial pressure (MAP, increased by 16 ± 4, versus saline, 3 ± 2 mmHg). Bilateral inhibition of the RTN neurons with the GABA(A) agonist muscimol (100 pmol in 50 nl) reduced resting ventilation (52 ± 34, versus saline, 250 ± 56 ml min(-1) kg(-1) with absolute values) and attenuated the respiratory response to hypercapnia and hypoxia. Muscimol injected into the RTN slightly reduced resting MAP (decreased by 13 ± 7, versus saline, increased by 3 ± 2 mmHg), without changing the effects of hypercapnia or hypoxia on MAP and heart rate. The results suggest that RTN neurons activate facilitatory mechanisms important to the control of ventilation in resting, hypoxic or hypercapnic conditions in conscious rats.
Asunto(s)
Presión Sanguínea/fisiología , N-Metilaspartato/farmacología , Respiración/efectos de los fármacos , Centro Respiratorio/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Estado de Conciencia/fisiología , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Masculino , Muscimol/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/efectos de los fármacosRESUMEN
BACKGROUND: Activation of GABA(B) receptors with baclofen into the lateral parabrachial nucleus (LPBN) induces ingestion of water and 0.3 M NaCl in fluid replete rats. However, up to now, no study has investigated the effects of baclofen injected alone or combined with GABA(B) receptor antagonist into the LPBN on water and 0.3 M NaCl intake in rats with increased plasma osmolarity (rats treated with an intragastric load of 2 M NaCl). Male Wistar rats with stainless steel cannulas implanted bilaterally into the LPBN were used. RESULTS: In fluid replete rats, baclofen (0.5 nmol/0.2 µl), bilaterally injected into the LPBN, induced ingestion of 0.3 M NaCl (14.3 ± 4.1 vs. saline: 0.2 ± 0.2 ml/210 min) and water (7.1 ± 2.9 vs. saline: 0.6 ± 0.5 ml/210 min). In cell-dehydrated rats, bilateral injections of baclofen (0.5 and 1.0 nmol/0.2 µl) into the LPBN induced an increase of 0.3 M NaCl intake (15.6 ± 5.7 and 21.5 ± 3.5 ml/210 min, respectively, vs. saline: 1.7 ± 0.8 ml/210 min) and an early inhibition of water intake (3.5 ± 1.4 and 6.7 ± 2.1 ml/150 min, respectively, vs. saline: 9.2 ± 1.4 ml/150 min). The pretreatment of the LPBN with 2-hydroxysaclofen (GABA(B) antagonist, 5 nmol/0.2 µl) potentiated the effect of baclofen on 0.3 M NaCl intake in the first 90 min of test and did not modify the inhibition of water intake induced by baclofen in cell-dehydrated rats. Baclofen injected into the LPBN did not affect blood pressure and heart rate. CONCLUSIONS: Thus, injection of baclofen into the LPBN in cell-dehydrated rats induced ingestion of 0.3 M NaCl and inhibition of water intake, suggesting that even in a hyperosmotic situation, the blockade of LPBN inhibitory mechanisms with baclofen is enough to drive rats to drink hypertonic NaCl, an effect independent of changes in blood pressure.
Asunto(s)
Baclofeno/farmacología , Deshidratación/psicología , Agonistas del GABA/farmacología , Puente/fisiología , Solución Salina Hipertónica , Animales , Presión Arterial/efectos de los fármacos , Baclofeno/administración & dosificación , Baclofeno/análogos & derivados , Ingestión de Líquidos , Lateralidad Funcional/fisiología , Agonistas del GABA/administración & dosificación , Antagonistas del GABA/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Concentración Osmolar , Ratas , Ratas WistarRESUMEN
Previous studies from our laboratory have shown that the pressor response to intracerebroventricular (icv) administered ANG II in normotensive rats or spontaneously hypertensive rats (SHRs) is attenuated by increased central H2O2 concentration, produced either by direct H2O2 icv injection or by increased endogenous H2O2 centrally in response to local catalase inhibition with 3-amino-1,2,4-triazole (ATZ). In the present study, we evaluated the effects of ATZ administered peripherally on arterial pressure and sympathetic and angiotensinergic activity in SHRs. Male SHRs weighing 280-330 g were used. Mean arterial pressure (MAP) and heart rate (HR) were recorded in conscious freely moving SHRs. Acute intravenous injection of ATZ (300 mg/kg of body weight) did not modify MAP and HR during the next 4 h, however, the treatment with ATZ (300 mg/kg of body weight twice per day) for 3 days reduced MAP (144 ± 6, vs. saline, 183 ± 13 mmHg), without changing HR. Intravenous hexamethonium (ganglionic blocker) produced a smaller decrease in MAP 4 h after ATZ (-25 ± 3, vs saline -38 ± 4 mmHg). Losartan (angiotensinergic AT1 receptor blocker) produced a significant depressor response 4 h after ATZ (-22 ± 4, vs. saline: -2 ± 4 mmHg) and in 3-day ATZ treated SHRs (-25 ± 5, vs. saline: -9 ± 4 mmHg). The results suggest that the treatment with ATZ reduces sympathetic activity in SHRs and simultaneously increases angiotensinergic activity.
Asunto(s)
Hipertensión , Triazoles , Ratas , Masculino , Animales , Ratas Endogámicas SHR , Amitrol (Herbicida)/farmacología , Triazoles/farmacología , Peróxido de Hidrógeno/farmacología , Presión Sanguínea , Frecuencia Cardíaca , Peso Corporal , Hipertensión/tratamiento farmacológicoRESUMEN
AIMS: Reactive oxygen species like hydrogen peroxide (H2O2) are produced endogenously and may participate in intra- and extracellular signaling, including modulation of angiotensin II responses. In the present study, we investigated the effects of chronic subcutaneous (sc) administration of the catalase inhibitor 3-amino-1,2,4-triazole (ATZ) on arterial pressure, autonomic modulation of arterial pressure, hypothalamic expression of AT1 receptors and neuroinflammatory markers and fluid balance in 2-kidney, 1clip (2K1C) renovascular hypertensive rats. MATERIALS AND METHODS: Male Holtzman rats with a clip occluding partially the left renal artery and chronic sc injections of ATZ were used. KEY FINDINGS: Subcutaneous injections of ATZ (600 mg/kg of body weight/day) for 9 days in 2K1C rats reduced arterial pressure (137 ± 8, vs. saline: 182 ± 8 mmHg). ATZ also reduced the sympathetic modulation and enhanced the parasympathetic modulation of pulse interval, reducing the sympatho-vagal balance. Additionally, ATZ reduced mRNA expression for interleukins 6 and IL-1ß, tumor necrosis factor-α, AT1 receptor (0.77 ± 0.06, vs. saline: 1.47 ± 0.26 fold change), NOX 2 (0.85 ± 0.13, vs. saline: 1.75 ± 0.15 fold change) and the marker of microglial activation, CD 11 (0.47 ± 0.07, vs. saline, 1.34 ± 0.15 fold change) in the hypothalamus of 2K1C rats. Daily water and food intake and renal excretion were only slightly modified by ATZ. SIGNIFICANCE: The results suggest that the increase of endogenous H2O2 availability with chronic treatment with ATZ had an anti-hypertensive effect in 2K1C hypertensive rats. This effect depends on decreased activity of sympathetic pressor mechanisms and mRNA expression of AT1 receptors and neuroinflammatory markers possibly due to reduced angiotensin II action.
Asunto(s)
Hipertensión Renovascular , Hipertensión , Enfermedades Renales , Ratas , Masculino , Animales , Hipertensión Renovascular/tratamiento farmacológico , Angiotensina II/farmacología , Catalasa , Peróxido de Hidrógeno/farmacología , Hipertensión/tratamiento farmacológico , Ratas Sprague-Dawley , ARN Mensajero , Presión SanguíneaRESUMEN
BACKGROUND: A growing body of evidence suggests that oxidative stress plays a role in the pathophysiology of hypertension. However, the involvement of the reactive oxygen species (ROS) in the commissural nucleus of the solitary tract (commNTS) in development the of hypertension remains unclear. METHOD: We evaluated the hemodynamic and sympathetic responses to acute inhibition of NADPH oxidase in the commNTS in renovascular hypertensive rats. Under anesthesia, male Holtzman rats were implanted with a silver clip around the left renal artery to induce 2-kidney 1-clip (2K1C) hypertension. After six weeks, these rats were anesthetized and instrumented for recording mean arterial pressure (MAP), renal blood flow (RBF), renal vascular resistance (RVR), and renal sympathetic nerve activity (RSNA) during baseline and after injection of apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor), NSC 23766 (RAC inhibitor) or saline into the commNTS. RESULTS: Apocynin into the commNTS decreased MAP, RSNA, and RVR in 2K1C rats. NSC 23766 into the commNTS decreased MAP and RSNA, without changing RVR in 2K1C rats. CONCLUSION: These results demonstrate that the formation of ROS in the commNTS is important to maintain sympathoexcitation and hypertension in 2K1C rats and suggest that NADPH oxidase in the commNTS could be a potential target for therapeutics in renovascular hypertension.
Asunto(s)
Hipertensión Renovascular , Hipertensión , Ratas , Masculino , Animales , Presión Arterial , Núcleo Solitario/metabolismo , NADP , Especies Reactivas de Oxígeno , Presión Sanguínea/fisiología , Riñón , Sistema Nervioso Simpático , Ratas Sprague-Dawley , NADPH Oxidasas/metabolismoRESUMEN
GABAA receptor activation with agonist muscimol in the lateral parabrachial nucleus (LPBN) induces 0.3 M NaCl intake. In the present study, we investigated water and 0.3 M NaCl intake in male adult rats treated with losartan (angiotensin AT1 receptor antagonist) or MeT-AVP (V1-type vasopressin receptor antagonist) combined with muscimol or methysergide (5-HT2 antagonist) into the LPBN in rats treated with intragastric 2 M NaCl. After 2 M NaCl load and bilateral injections of muscimol (0.5 nmol/0.2 µL) into the LPBN, rats ingested water and 0.3 M NaCl. The pre-treatment of the LPBN with MeT-AVP (1 nmol/0.2 µL) but not losartan (50 µg/0.2 µL) in muscimol treated rats reduced 0.3 M NaCl intake. The pre-treatment of the LPBN with MeT-AVP did not modify the increased 0.3 M NaCl intake in rats treated with methysergide (4 µg/0.2 µL), suggesting that the effect of MeT-AVP was not due to non-specific inhibition of ingestive behavior. The results suggest that endogenous vasopressin in the LPBN facilitates the effects of GABAergic activation driving cell-dehydrated male rats to ingest 0.3 M NaCl.
Asunto(s)
Núcleos Parabraquiales , Antagonistas de Receptores de Angiotensina , Animales , Ingestión de Líquidos , Losartán/farmacología , Masculino , Metisergida/farmacología , Muscimol/farmacología , Núcleos Parabraquiales/fisiología , Ratas , Receptores de GABA-A/metabolismo , Receptores de Vasopresinas , Cloruro de Sodio/farmacología , Agua/farmacologíaRESUMEN
The idea that the nervous system communicates with the immune system to regulate physiological and pathological processes is not new. However, there is still much to learn about how these interactions occur under different conditions. The carotid body (CB) is a sensory organ located in the neck, classically known as the primary sensor of the oxygen (O2) levels in the organism of mammals. When the partial pressure of O2 in the arterial blood falls, the CB alerts the brain which coordinates cardiorespiratory responses to ensure adequate O2 supply to all tissues and organs in the body. A growing body of evidence, however, has demonstrated that the CB is much more than an O2 sensor. Actually, the CB is a multimodal sensor with the extraordinary ability to detect a wide diversity of circulating molecules in the arterial blood, including inflammatory mediators. In this review, we introduce the literature supporting the role of the CB as a critical component of neuroimmune interactions. Based on ours and other studies, we propose a novel neuroimmune pathway in which the CB acts as a sensor of circulating inflammatory mediators and, in conditions of systemic inflammation, recruits a sympathetic-mediated counteracting mechanism that appears to be a protective response.
Asunto(s)
Cuerpo Carotídeo , Animales , Neuroinmunomodulación , Oxígeno/metabolismo , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Mamíferos/metabolismoRESUMEN
A rise in arterial Pco(2) stimulates breathing and sympathetic activity to the heart and blood vessels. In the present study, we investigated the involvement of the retrotrapezoid nucleus (RTN) and glutamatergic mechanisms in the Bötzinger/C1 region (Bötz/C1) in these responses. Splanchnic sympathetic nerve discharge (sSND) and phrenic nerve discharge (PND) were recorded in urethane-anesthetized, sino-aortic-denervated, vagotomized, and artificially ventilated rats subjected to hypercapnia (end-expiratory CO(2) from 5% to 10%). Phrenic activity was absent at end-expiratory CO(2) of 4%, and strongly increased when end-expiratory CO(2) reached 10%. Hypercapnia also increased sSND by 103 ± 7%. Bilateral injections of the GABA-A agonist muscimol (2 mM) into the RTN eliminated the PND and blunted the sSND activation (Δ = +56 ± 8%) elicited by hypercapnia. Injections of NMDA receptor antagonist AP-5 (100 mM), non-NMDA receptor antagonist 6,7-dinitro-quinoxaline-2,3-dione (DNQX; 100 mM) or metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG; 100 mM) bilaterally into the Bötz/C1 reduced PND (Δ = +43 ± 7%, +52 ± 6% or +56 ± 11%, respectively). MCPG also reduced sSND (Δ = +41 ± 7%), whereas AP-5 and DNQX had no effect. In conclusion, the increase in sSND caused by hypercapnia depends on increased activity of the RTN and on metabotropic receptors in the Bötz/C1, whereas PND depends on increased RTN activity and both ionotropic and metabotropic receptors in the Bötz/C1.