RESUMO
BACKGROUND/AIMS: Aortic stenosis-induced chronic pressure overload leads to cardiac dysfunction and congestive heart failure. The pathophysiological mechanisms of the myocardial impairment are multifactorial and include maladaptive ß-adrenergic signaling. Exercise training (ET) has been used as a non-pharmacological therapy for heart failure management. The present study tested the hypothesis that exercise training attenuates diastolic dysfunction through ß-adrenergic signaling preservation. METHODS: Wistar rats were submitted to ascending aortic stenosis (AS) surgery, and after 18 weeks, a moderate aerobic exercise training protocol was performed for ten weeks. RESULTS: ET attenuated diastolic dysfunction, evaluated by echocardiogram and isolated papillary muscle (IPM) assay. Also, ET reduced features of heart failure, cross-sectional cardiomyocyte area, and exercise intolerance, assessed by treadmill exercise testing. The ß2 adrenergic receptor protein expression was increased in AS rats independently of exercise. Interestingly, ET restored the protein levels of phosphorylated phospholamban at Serine 16 and preserved the ß-adrenergic receptor responsiveness as visualized by the lower myocardial compliance decline and time to 50% tension development and relaxation during ß-adrenergic stimulation in the IPM than untrained rats. Additionally, AS rats presented higher levels of TNFα and iNOS, which were attenuated by ET. CONCLUSION: Moderate ET improves exercise tolerance, reduces heart failure features, and attenuates diastolic dysfunction. In the myocardium, ET decreases the cross-sectional area of the cardiomyocyte and preserves the ß-adrenergic responsiveness, which reveals that the adjustments in ß-adrenergic signaling contribute to the amelioration of cardiac dysfunction by mild exercise training in aortic stenosis rats.
Assuntos
Estenose Aórtica Supravalvular/metabolismo , Insuficiência Cardíaca Diastólica/terapia , Miócitos Cardíacos/metabolismo , Condicionamento Físico Animal/fisiologia , Receptores Adrenérgicos beta/metabolismo , Animais , Estenose Aórtica Supravalvular/terapia , Proteínas de Ligação ao Cálcio/metabolismo , Ecocardiografia , Teste de Esforço , Masculino , Miocárdio/metabolismo , Miócitos Cardíacos/fisiologia , Óxido Nítrico Sintase Tipo II/metabolismo , Músculos Papilares/fisiologia , Fosforilação , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/fisiologia , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: We investigated the effects of early ovarian hormones deprivation on morphology and cardiac function and the effects of aerobic training on these parameters, in old rats. METHODS: Female Wistar rats (Nâ¯=â¯48) were divided into two groups, at 10â¯weeks of life: early ovarian hormones deprivation by ovariectomy (OVX; Nâ¯=â¯24) and sham (SHAM; Nâ¯=â¯24). Between weeks 62 and 82, 12 animals of each group underwent aerobic training (OVX-T and SHAM-T, Nâ¯=â¯12). At the end of week 82, all were evaluated by echocardiography, cardiac function (Langendorff technique) and cardiac ß-adrenergic receptor expression quantification. RESULTS: Echocardiography showed slight changes in morphology between OVX and SHAM groups. OVX group (Δâ¯=â¯101⯱â¯4.7â¯mmHg) showed higher values for maximal left intraventricular pressure in response to dobutamine, when compared to SHAM group (Δâ¯=â¯55⯱â¯11.8â¯mmHg). Both OVX-T (Δâ¯=â¯70⯱â¯4.0â¯mmHg) and SHAM-T (Δâ¯=â¯22⯱â¯6.6â¯mmHg) groups showed a reduction in this response. While, ß-adrenergic receptor expression was not different between the untrained groups, SHAM-T (0.23⯱â¯0.02â¯AU) and OVX-T (0.29⯱â¯0.01â¯AU), showed decreased expression of these receptors. CONCLUSION: Early ovarian hormones deprivation associated with aging, promotes discrete changes in cardiac morphology and increasing cardiac contractility. Aerobic training decreases ß-adrenergic receptors expression, influencing the cardiac contractility.
Assuntos
Hormônios Esteroides Gonadais/fisiologia , Coração/fisiologia , Contração Miocárdica/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Ecocardiografia , Feminino , Ovariectomia , Ratos Wistar , Receptores Adrenérgicos beta/fisiologia , Pressão VentricularRESUMO
It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (â1- and ß-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and â1-AR and ß-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by â1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of ß-AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between ß-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs.
Assuntos
Glucose/metabolismo , Hipertensão Portal/metabolismo , Fígado/metabolismo , Receptor Tipo 1 de Angiotensina/fisiologia , Receptores Adrenérgicos alfa/fisiologia , Receptores Adrenérgicos beta/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Fígado/efeitos dos fármacos , Losartan/farmacologia , Masculino , Prazosina/farmacologia , Propranolol/farmacologia , Ratos Wistar , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Fatores de TempoRESUMO
We investigated the effects of angiotensin-converting enzyme (ACE) inhibition and aerobic physical training on the heart of old female rats (82-wk-old) submitted to premature ovarian failure (10-wk.-old). We used different approaches: morphology and function by echocardiography, reactivity of the coronary bed and left ventricular contractibility (Langendorff Technique). Female Wistar ovariectomized (OVX) rats (n=42) were assigned to one of four groups: OVX, vehicle treated only; OVX-EM, Enalapril Maleate only (EM, 10mg·kg-1·d-1); OVX-T, aerobic trained only; and OVX-EMT, treated with Enalapril Maleate and aerobic trained. Both Enalapril Maleate treatment and aerobic training were done in the last 20weeks of the experimental protocol. When compared to the OVX group, the OVX-EM group showed lower values of wall thickness and left ventricular (LV) mass, lower values of coronary bed reactivity and reduced maximum response of LV contractility to dobutamine, while the OVX-T group showed lower values of LV wall thickness, increase in end-systolic volume, reduced maximum response of LV contractility to dobutamine, and left intraventricular pressure due to increased flow. The combination of treatments (EM and aerobic physical training) did not promote additional important effects on the parameters evaluated. Our results suggest similar beneficial effects of physical training and EM treatment on the morphology and cardiac function in old female rats submitted to premature ovarian failure. Although the causes of these benefits are still unknown, both treatments have promoted a decrease in cardiac contractility, and the reduced ß1-adrenergic sensitivity suggests that both treatments may attenuate the sympathetic effect on the heart.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Enalapril/farmacologia , Coração/efeitos dos fármacos , Condicionamento Físico Animal , Insuficiência Ovariana Primária/fisiopatologia , Animais , Feminino , Coração/fisiologia , Contração Miocárdica/efeitos dos fármacos , Miocárdio/patologia , Ovariectomia , Insuficiência Ovariana Primária/patologia , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/fisiologia , Função Ventricular EsquerdaRESUMO
In the heart, catecholamine effects occur by activation of beta-adrenergic receptors (ß-ARs), mainly the beta 1 (ß1-AR) and beta 2 (ß2-AR) subtypes, both of which couple to the Gs protein that activates the adenylyl cyclase signaling pathway. The ß2-ARs can also couple to the Gi protein that counterbalances the effect of the Gs protein on cyclic adenosine monophosphate production and activates the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In several cardiovascular disorders, including heart failure, as well as in aging and in animal models of environmental stress, a reduction in the ß1/ß2-AR ratio and activation of the ß2-AR-Gi-PI3K-Akt signaling pathway have been observed. Recent studies have shown that sirtuins modulate certain organic processes, including the cellular stress response, through activation of the PI3K-Akt signaling pathway and of downstream molecules such as p53, Akt, HIF1-α, and nuclear factor-kappa B. In the heart, SIRT1, SIRT3, and ß2-ARs are crucial to the regulation of the cardiomyocyte energy metabolism, oxidative stress, reactive oxygen species production, and autophagy. SIRT1 and the ß2-AR-Gi complex also control signaling pathways of cell survival and death. Here, we review the role played by ß2-ARs and sirtuins during aging, heart failure, and adaptation to stress, focusing on the putative interplay between the two. That relationship, if proven, merits further investigation in the context of cardiac function and dysfunction.
Assuntos
Envelhecimento/metabolismo , Insuficiência Cardíaca/metabolismo , Receptores Adrenérgicos beta/fisiologia , Transdução de Sinais/fisiologia , Sirtuínas/metabolismo , Estresse Psicológico/metabolismo , Adaptação Fisiológica/fisiologia , Adaptação Psicológica/fisiologia , Envelhecimento/psicologia , Animais , Insuficiência Cardíaca/psicologia , Humanos , Miócitos Cardíacos/metabolismo , Estresse Psicológico/psicologiaRESUMO
It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (∝1- and β-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and ∝1-AR and β-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by ∝1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of β-AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between β-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs.
Assuntos
Animais , Masculino , Receptores Adrenérgicos alfa/fisiologia , Receptores Adrenérgicos beta/fisiologia , Receptor Tipo 1 de Angiotensina/fisiologia , Glucose/metabolismo , Hipertensão Portal/metabolismo , Fígado/metabolismo , Propranolol/farmacologia , Fatores de Tempo , Prazosina/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Ratos Wistar , Antagonistas Adrenérgicos beta/farmacologia , Losartan/farmacologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Fígado/efeitos dos fármacosRESUMO
Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH) is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However, the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region of the hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5µg/side) 20min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally, the administration of MPH+Timolol (1µg/side) or MPH+SCH23390 (1.5µg/side) intra-CA1 20min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both ß-adrenergic and D1/D5 dopaminergic receptors.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Dopamina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Metilfenidato/farmacologia , Receptores Adrenérgicos beta/fisiologia , Receptores Dopaminérgicos/fisiologia , Antagonistas Adrenérgicos beta/administração & dosagem , Animais , Benzazepinas/administração & dosagem , Benzazepinas/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Antagonistas de Dopamina/administração & dosagem , Medo/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Dopamina D1/antagonistas & inibidores , Timolol/administração & dosagem , Timolol/farmacologiaRESUMO
OBJECTIVE: Dopamine is an immunomodulatory neurotransmitter. In the skin, keratinocytes and macrophages produce proinflammatory cytokines and metalloproteinases (MMPs) which participate in wound healing. These cells have a catecholaminergic system that modulates skin pathophysiologic processes. We have demonstrated that dopamine modulates cytokine production in keratinocytes via dopaminergic and adrenergic receptors (ARs). The aim of this study was to evaluate the effect of dopamine and its interaction with ß-ARs in human HaCaT keratinocytes and THP-1 macrophages. We evaluated the production of inflammatory mediators implicated in wound healing. METHODS: Cells were stimulated with dopamine in the absence or presence of the ß-adrenergic antagonist propranolol. Wound closure, MMP activity, and the production of IL-8, IL-1ß, and IκB/NFκB pathway activation were determined in stimulated cells. RESULTS: Dopamine did not affect the wound closure in human keratinocytes, but diminished the propranolol stimulatory effect, thus delaying cell migration. Similarly, dopamine significantly decreased MMP-9 activity and the propranolol-induced MMP activity. Dopamine significantly increased the p65-NFκB subunit levels in the nuclear extracts, which were reduced in the presence of propranolol in keratinocytes. On the other hand, dopamine significantly increased MMP-9 activity in THP-1 macrophages, but did not modify the propranolol-increased enzymatic activity. Dopamine significantly increased IL-8 production in human macrophages, an effect that was partially reduced by propranolol. Dopamine did not modify the p65-NFκB levels in the nuclear extracts in THP-1 macrophages. CONCLUSION: We suggest that the effect of dopamine via ß-ARs depends on the physiological condition and the cell type involved, thus contributing to either improve or interfere with the healing process.
Assuntos
Dopamina/farmacologia , Queratinócitos/fisiologia , Macrófagos/fisiologia , Receptores Adrenérgicos beta/fisiologia , Cicatrização/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Queratinócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Cicatrização/efeitos dos fármacosRESUMO
Beta-adrenergic receptor (ßAR)-dependent blood vessel relaxation is impaired in older animals and G protein activation has been suggested as the causative mechanism. Here, we investigated the role of ßAR subtypes (ß1AR, ß2AR, and ß3AR) and cAMP in maturation-dependent vasorelaxation impairment. Aortic rings from 15 Sprague-Dawley male rats (3 or 9 weeks old) were harvested and left intact or denuded of the endothelium. Vascular relaxation in aortic rings from younger and older groups was compared in the presence of ßAR subtype agonists and antagonists along with cAMP and cGMP antagonists. Isolated aortic rings were used to evaluate relaxation responses, protein expression was evaluated by western blot or real time PCR, and metabolites were measured by ELISA. Expression of ßAR subtypes and adenylyl cyclase was assessed, and cAMP activity was measured in vascular tissue from both groups. Isoproterenol- and BRL744-dependent relaxation in aortic rings with and without endothelium from 9-week-old rats was impaired compared with younger rats. The ß1AR antagonist CGP20712A (10-7 M) did not affect isoproterenol or BRL744-dependent relaxation in arteries from either group. The ß2AR antagonist ICI-118,551 (10-7 M) inhibited isoproterenol-dependent aortic relaxation in both groups. The ß3AR antagonist SR59230A (10-7 M) inhibited isoproterenol- and BRL744-dependent aortic ring relaxation in younger but not in older rats. All ßAR subtypes were expressed in both groups, although ß3AR expression was lower in the older group. Adenylyl cyclase (SQ 22536) or protein kinase A (H89) inhibitors prevented isoproterenol-induced relaxation in younger but not in older rats. Production of cAMP was reduced in the older group. Adenylyl cyclase III and RyR3 protein expression was higher in the younger group. In conclusion, altered expression of ß3AR and adenylyl cyclase III may be responsible for reduced cAMP production in the older group.
Assuntos
Inibidores de Adenilil Ciclases/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Adenilil Ciclases/fisiologia , Fatores Etários , Albuterol/farmacologia , Animais , Aorta Torácica/fisiologia , Western Blotting , AMP Cíclico/análise , AMP Cíclico/metabolismo , Dobutamina/farmacologia , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Isoproterenol/farmacologia , Masculino , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptores Adrenérgicos beta/fisiologia , Valores de Referência , Fatores de TempoRESUMO
Previous studies from our laboratory have demonstrated that a single bout of moderate exercise stimulates macrophage function, increasing phagocytic capacity, and production of hydrogen peroxide and nitric oxide (NOË) through nuclear factor kappa B activation. In this work, we investigated the role of α- and ß-adrenoreceptors on the function of monocyte/macrophages during rest and exercise. Adult male Wistar rats were i.p. administered (100 µL/100 g) with specific adrenergic antagonists before an acute moderate exercise bout: prazosin (α1-specific antagonist 2 mg/kg), propranolol (unspecific ß1/ß2 antagonist 10 mg/kg), double blockade (α1 and ß1/ß2), or phosphate-buffered saline (control). Acute exercise consisted in a single swimming session of moderate intensity (5% body weight overload on the chest) for 60 min. Control groups (rest) received the same antagonists and were killed 60 min after drug administration. Exercise increased phagocytic capacity (1.7-fold, p < 0.05), NOË production (5.24 fold, p < 0.001), and inducible nitric oxide synthase (NOS2) expression (by 58.1%), thus suggesting macrophage activation. The ß-adrenoreceptor blockade did not change this behavior. In resting animals, α1 antagonist, as well as the double (α1/ß) blockade, however, further increased phagocytic capacity (by up to 261%, p < 0.001), NOË production (by up to 328%, p < 0.001), and the expressions of NOS2 (by 182%, p < 0.001) and HSP70 (by 42.5%, p < 0.01) suggesting a tonic inhibitory effect of α1 stimulation on macrophage activation. In exercised animals, α1-blockade showed similar enhancing effect on phagocytic indices and expressions of NOS and HSP70, particularly in double-blocked groups, although NOË production was found to be reduced in exercised animals submitted to both α- and ß-blockade. Redox (glutathione) status and lipoperoxidation were evaluated in all test groups and approximately paralleled macrophage NOË production. We suggest the prevalence of a peripheral α1-adrenoreceptor inhibitory tonus that limits macrophage responsiveness but operates differently after physical exercise.