RESUMO
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.
Assuntos
Hipertensão , Triazóis , Ratos , Masculino , Animais , Ratos Endogâmicos SHR , Amitrol (Herbicida)/farmacologia , Triazóis/farmacologia , Peróxido de Hidrogênio/farmacologia , Pressão Sanguínea , Frequência Cardíaca , Peso Corporal , Hipertensão/tratamento farmacológicoRESUMO
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.
Assuntos
Hipertensão Renovascular , Hipertensão , Nefropatias , Ratos , Masculino , Animais , Hipertensão Renovascular/tratamento farmacológico , Angiotensina II/farmacologia , Catalase , Peróxido de Hidrogênio/farmacologia , Hipertensão/tratamento farmacológico , Ratos Sprague-Dawley , RNA Mensageiro , Pressão SanguíneaRESUMO
Intracerebroventricular (icv) injection of hydrogen peroxide (H2O2) or the increase of endogenous H2O2 centrally produced by catalase inhibition with 3-amino-1,2,4-triazole (ATZ) injected icv reduces the pressor responses to central angiotensin II (ANG II) in normotensive rats. In the present study, we investigated the changes in the arterial pressure and in the pressor responses to ANG II icv in spontaneously hypertensive rats (SHRs) and 2-kidney, 1-clip (2K1C) hypertensive rats treated with H2O2 injected icv or ATZ injected icv or intravenously (iv). Adult male SHRs or Holtzman rats (n = 5-10/group) with stainless steel cannulas implanted in the lateral ventricle were used. In freely moving rats, H2O2 (5 µmol/1 µl) or ATZ (5 nmol/1 µl) icv reduced the pressor responses to ANG II (50 ng/1 µl) icv in SHRs (11 ± 3 and 17 ± 4 mmHg, respectively, vs. 35 ± 6 mmHg) and 2K1C hypertensive rats (3 ± 1 and 16 ± 3 mmHg, respectively, vs. 26 ± 2 mmHg). ATZ (3.6 mmol/kg of body weight) iv alone or combined with H2O2 icv also reduced icv ANG II-induced pressor response in SHRs and 2K1C hypertensive rats. Baseline arterial pressure was also reduced (-10 to -15 mmHg) in 2K1C hypertensive rats treated with H2O2 icv and ATZ iv alone or combined and in SHRs treated with H2O2 icv alone or combined with ATZ iv. The results suggest that exogenous or endogenous H2O2 acting centrally produces anti-hypertensive effects impairing central pressor mechanisms activated by ANG II in SHRs or 2K1C hypertensive rats.
Assuntos
Amitrol (Herbicida)/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Peróxido de Hidrogênio/administração & dosagem , Hipertensão/tratamento farmacológico , Oxidantes/administração & dosagem , Angiotensina II , Animais , Catalase/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Infusões Intraventriculares , Masculino , Ratos Endogâmicos SHRRESUMO
Intracerebroventricular (icv) injection of hydrogen peroxide (H2O2), a reactive oxygen species, or the blockade of catalase (enzyme that degrades H2O2 into H2O and O2) with icv injection of 3-amino-1,2,4-triazole (ATZ) reduces the pressor effects of angiotensin II also injected icv. In the present study, we investigated the effects of ATZ injected icv or intravenously (iv) on the pressor responses induced by icv injections of the cholinergic agonist carbachol, which similar to angiotensin II induces pressor responses that depend on sympathoexcitation and vasopressin release. In addition, the effects of H2O2 icv on the pressor responses to icv carbachol were also tested to compare with the effects of ATZ. Normotensive non-anesthetized male Holtzman rats (280-300 g, n = 8-9/group) with stainless steel cannulas implanted in the lateral ventricle were used. Previous injection of ATZ (5 nmol/1 µl) or H2O2 (5 µmol/1 µl) icv similarly reduced the pressor responses induced by carbachol (4 nmol/1 µl) injected icv (13 ± 4 and 12 ± 4 mmHg, respectively, vs. vehicle + carbachol: 30 ± 5 mmHg). ATZ (3.6 mmol/kg of body weight) injected iv also reduced icv carbachol-induced pressor responses (21 ± 2 mmHg). ATZ icv or iv and H2O2 icv injected alone produced no effect on baseline arterial pressure. The treatments also produced no significant change of heart rate. The results show that ATZ icv or iv reduced the pressor responses to icv carbachol, suggesting that endogenous H2O2 acting centrally inhibits the pressor mechanisms (sympathoactivation and/or vasopressin release) activated by central cholinergic stimulation.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Catalase/farmacologia , Hipertensão/fisiopatologia , Amitrol (Herbicida)/farmacologia , Angiotensina II , Animais , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Hipertensão/tratamento farmacológico , Injeções Intraventriculares , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Vasoconstritores/farmacologia , VasopressinasRESUMO
Angiotensin II (ANG II) is a typical facilitatory stimulus for sodium appetite. Surprisingly, hyperosmolarity and central cholinergic stimulation, two classical antinatriorexigenic stimuli, also facilitate NaCl intake when they are combined with injections of the α2-adrenoceptor/imidazoline agonist moxonidine into the lateral parabrachial nucleus (LPBN). In the present study, we tested the relative importance of central angiotensinergic and cholinergic mechanisms for the control of water and NaCl intake by combining different dipsogenic or natriorexigenic stimuli with moxonidine injection into the LPBN. Adult male Holtzman rats (n=9-10/group) with stainless steel cannulas implanted in the lateral ventricle and LPBN were used. Bilateral injections of moxonidine (0.5 nmol) into the LPBN increased water and 0.3M NaCl intake in rats that received furosemide+captopril injected subcutaneously, ANG II (50ng) or carbachol (cholinergic agonist, 4 nmol) injected intracerebroventricularly (icv) or 2M NaCl infused intragastrically (2ml/rat). Losartan (AT1 antagonist, 100µg) or atropine (muscarinic antagonist, 20 nmol) injected icv abolished the effects on water and 0.3M NaCl of moxonidine combined to either 2M NaCl intragastrically or carbachol icv. However, atropine icv did not change 0.3M NaCl intake produced by direct central action of ANG II like that induced by ANG II icv or furosemide+captopril combined with moxonidine into the LPBN. The results suggest that different stimuli, including hyperosmolarity and central cholinergic stimulation, share central angiotensinergic activation as a common mechanism to facilitate sodium intake, particularly when they are combined with deactivation of the LPBN inhibitory mechanisms.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Núcleos Parabraquiais/efeitos dos fármacos , Núcleos Parabraquiais/fisiologia , Cloreto de Sódio/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Atropina/farmacologia , Captopril/farmacologia , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Líquidos/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Furosemida/farmacologia , Imidazóis/farmacologia , Losartan/farmacologia , Masculino , Antagonistas Muscarínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Fatores de TempoRESUMO
Facilitatory and inhibitory mechanisms in the central nucleus of the amygdala (CeA) and the lateral parabrachial nucleus (LPBN), respectively, are important for the control of sodium and water intake. Here we investigated the importance of the opioid mechanisms in the CeA for water and 0.3M NaCl intake in euhydrated or hyperosmotic rats treated with injections of muscimol (GABAA agonist) or moxonidine (α2 adrenergic/imidazoline agonist) into the LPBN, respectively. Male Holtzman rats (n=4-8/group) with stainless steel cannulas implanted bilaterally in the CeA and in the LPBN were used. The ingestion of 0.3M NaCl and water by euhydrated rats treated with muscimol (0.5nmol/0.2µl) into the LPBN (29.4±2.7 and 15.0±2.4ml/4h, respectively) was abolished by the previous injections of naloxone (opioid antagonist, 40µg/0.2µl) into the CeA (0.7±0.3 and 0.3±0.1ml/4h, respectively). The ingestion of 0.3M NaCl by rats treated with intragastric 2M NaCl (2ml/rat) combined with moxonidine (0.5nmol/0.2µl) into the LPBN (17.0±3.8ml/2h) was also strongly reduced by the previous injections of naloxone into the CeA (3.2±2.5ml/2h). Sucrose intake was not affected by naloxone injections into the CeA, which minimized the possibility of non-specific inhibition of ingestive behaviors with this treatment. The present results suggest that opioid mechanisms in the CeA are essential for hypertonic NaCl intake when the LPBN inhibitory mechanisms are deactivated or attenuated with injections of muscimol or moxonidine in this area.
Assuntos
Analgésicos Opioides/metabolismo , Núcleo Central da Amígdala/fisiologia , Vias Neurais/fisiologia , Núcleos Parabraquiais/fisiologia , Sódio/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Núcleo Central da Amígdala/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Líquidos/fisiologia , Agonistas de Receptores de GABA-A/farmacologia , Imidazóis/farmacologia , Masculino , Muscimol/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Vias Neurais/efeitos dos fármacos , Núcleos Parabraquiais/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sódio na DietaRESUMO
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.
Assuntos
Apetite , Comportamento de Doença , Receptores Adrenérgicos alfa 2/metabolismo , Sódio/metabolismo , Animais , Lipopolissacarídeos/toxicidade , Equilíbrio HidroeletrolíticoRESUMO
The lateral parabrachial nucleus (LPBN) and the central nucleus of the amygdala (CeA) are important central areas for the control of sodium appetite. In the present study, we investigated the importance of the facilitatory mechanisms of the CeA on NaCl and water intake produced by the deactivation of LPBN inhibitory mechanisms. Male Holtzman rats (n=7-14) with stainless steel cannulas implanted bilaterally in the CeA and LPBN were used. Bilateral injections of moxonidine (α2-adrenoceptor/imidazoline agonist, 0.5 nmol/0.2 µl) into the LPBN increased furosemide+captopril-induced 0.3M NaCl (29.7 ± 7.2, vs. vehicle: 4.4 ± 1.6 ml/2h) and water intake (26.4 ± 6.7, vs. vehicle: 8.2 ± 1.6 ml/2h). The GABAA agonist muscimol (0.25 nmol/0.2 µl) injected bilaterally into the CeA abolished the effects of moxonidine into the LPBN on 0.3M NaCl (2.8 ± 1.6 ml/2h) and water intake (3.3 ± 2.3 ml/2h). Euhydrated rats treated with muscimol (0.5 nmol/0.2 µl) into the LPBN also ingested 0.3M NaCl (19.1 ± 6.4 ml/4h) and water (8.8 ± 3.2 ml/4h). Muscimol (0.5 nmol/0.2 µl) into the CeA also abolished 0.3M NaCl (0.1 ± 0.04 ml/4h) and water intake (0.1 ± 0.02 ml/4h) in euhydrated treated with muscimol into the LPBN. The present results show that neuronal deactivation of the CeA abolishes NaCl intake produced by the blockade of LPBN inhibitory mechanisms, suggesting an interaction between facilitatory mechanisms of the CeA and inhibitory mechanisms of the LPBN in the control of NaCl intake.
Assuntos
Núcleo Central da Amígdala/fisiologia , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Núcleos Parabraquiais/fisiologia , Sódio/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Captopril/farmacologia , Núcleo Central da Amígdala/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Furosemida/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Imidazóis/farmacologia , Masculino , Muscimol/farmacologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Ratos Sprague-Dawley , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Fatores de TempoRESUMO
Important inhibitory mechanisms for the control of water and sodium intake are present in the lateral parabrachial nucleus (LPBN). Opioid receptors are expressed by LPBN neurons and injections of ß-endorphin (nonspecific opioid receptor agonist) in this area induce 0.3M NaCl and water intake in satiated rats. In the present study, we investigated the effects of the injections of endomorphin-1 (µ opioid receptor agonist) alone or combined with the blockade of µ, κ or δ opioid receptors into the LPBN on 0.3M NaCl and water intake induced by subcutaneous injections of the diuretic furosemide (FURO) combined with low dose of the angiotensin converting enzyme inhibitor captopril (CAP). Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN were used. Bilateral injections of endomorphin-1 (0.1, 0.25, 0.5, 1.0, 2.0 and 4.0nmol/0.2µl) into the LPBN increased 0.3M NaCl and water intake induced by FURO+CAP. The previous blockade of µ opioid receptor with CTAP (1.0nmol/0.2µl) into the LPBN reduced the effect of endomorphin-1 on FURO+CAP-induced 0.3M NaCl. GNTI (κ opioid receptor antagonist; 2.0nmol/0.2µl) and naltrindole (δ opioid receptor antagonist; 2.0nmol/0.2µl) injected into the LPBN did not change the effects of endomorphin-1 on FURO+CAP-induced 0.3M NaCl. The results suggest that µ opioid receptors in the LPBN are involved in the control of sodium intake.
Assuntos
Regulação do Apetite/fisiologia , Ingestão de Líquidos/fisiologia , Núcleos Parabraquiais/metabolismo , Receptores Opioides mu/metabolismo , Sódio na Dieta , Analgésicos Opioides/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Regulação do Apetite/efeitos dos fármacos , Diuréticos/farmacologia , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Água Potável , Masculino , Antagonistas de Entorpecentes/farmacologia , Oligopeptídeos/farmacologia , Núcleos Parabraquiais/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Cloreto de SódioRESUMO
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.