RESUMO
The aim was to investigate the long-term effects of metformin ingestion on high-intensity interval training on performance, glycogen concentration (GC), GLUT-4 content, and metabolomics outcomes in rats. Fifty male Wistar rats were randomly divided into baseline, metformin (500 mg daily), and control groups. Training consisted of 4 sets of 10 jumps with 30 s of passive recovery per day, 5 days/week for 8 weeks. The intensity equivalent was 50% of body mass (BM) in the first four weeks and 70% of BM in the last four weeks. The animals were submitted to a weekly jump test until exhaustion at 50% of BM. Serum and tissues were collected at baseline and after 4 and 8 weeks for biochemical and metabolomics analysis. The number of jumps increased in the Control group without a significant difference between groups at 4 and 8 weeks. GLUT4 was lower in the gastrocnemius muscle in the Metformin at the fourth week compared to Control (P=0.03) and compared to Metformin (P=0.02) and Control (P=0.01) at eight weeks. Hepatic and soleus GC were not altered by metformin. Gastrocnemius GC was lower after 8 weeks in the Metformin group compared to Control (P=0.01). Significantly lower levels of pyruvate and phenylalanine and higher levels of ethanol, formate, betaine, very low-density lipoprotein, low-density lipoprotein, and creatine were found in the Metformin compared to the Control. Although chronic administration of metformin decreased food intake and negatively influenced the synthesis of muscle glycogen, it did not significantly change physical performance compared to the Control.
Assuntos
Transportador de Glucose Tipo 4 , Glicogênio , Treinamento Intervalado de Alta Intensidade , Hipoglicemiantes , Metabolômica , Metformina , Condicionamento Físico Animal , Animais , Masculino , Ratos , Transportador de Glucose Tipo 4/metabolismo , Glicogênio/metabolismo , Glicogênio/análise , Treinamento Intervalado de Alta Intensidade/métodos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/administração & dosagem , Espectroscopia de Ressonância Magnética/métodos , Metformina/farmacologia , Metformina/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Condicionamento Físico Animal/fisiologia , Desempenho Físico Funcional , Distribuição Aleatória , Ratos Wistar , Fatores de TempoRESUMO
The aim was to investigate the long-term effects of metformin ingestion on high-intensity interval training on performance, glycogen concentration (GC), GLUT-4 content, and metabolomics outcomes in rats. Fifty male Wistar rats were randomly divided into baseline, metformin (500 mg daily), and control groups. Training consisted of 4 sets of 10 jumps with 30 s of passive recovery per day, 5 days/week for 8 weeks. The intensity equivalent was 50% of body mass (BM) in the first four weeks and 70% of BM in the last four weeks. The animals were submitted to a weekly jump test until exhaustion at 50% of BM. Serum and tissues were collected at baseline and after 4 and 8 weeks for biochemical and metabolomics analysis. The number of jumps increased in the Control group without a significant difference between groups at 4 and 8 weeks. GLUT4 was lower in the gastrocnemius muscle in the Metformin at the fourth week compared to Control (P=0.03) and compared to Metformin (P=0.02) and Control (P=0.01) at eight weeks. Hepatic and soleus GC were not altered by metformin. Gastrocnemius GC was lower after 8 weeks in the Metformin group compared to Control (P=0.01). Significantly lower levels of pyruvate and phenylalanine and higher levels of ethanol, formate, betaine, very low-density lipoprotein, low-density lipoprotein, and creatine were found in the Metformin compared to the Control. Although chronic administration of metformin decreased food intake and negatively influenced the synthesis of muscle glycogen, it did not significantly change physical performance compared to the Control.
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Introduction: Microbial systems, such as Escherichia coli, as host recombinant expression is the most versatile and the cheapest system for protein production, however, several obstacles still remain, such as recovery of soluble and functional proteins from inclusion bodies, elimination of lipopolysaccharides (LPS) contamination, incomplete synthesis, degradation by proteases, and the lack of post-translational modifications, which becomes even more complex when comes to membrane proteins, because they are difficult not only to produce but also to keep in solution in its active state. T-cell Immunoglobulin and Mucin domain 3 (TIM-3) is a type I transmembrane protein that is predominantly expressed on the surface of T lymphocytes, natural killer (NK) cells, dendritic cells, and macrophages, playing a role as a negative immune checkpoint receptor. TIM-3 comprises a single ectodomain for interaction with immune system soluble and cellular components, a transmembrane domain, and a cytoplasmic tail, responsible for the binding of signaling and scaffolding molecules. TIM-3 pathway holds potential as a therapeutic target for immunotherapy against tumors, autoimmunity, chronic virus infections, and various malignancies, however, many aspects of the biology of this receptor are still incompletely understood, especially regarding its ligands. Methods: Here we overcome, for the first time, the challenge of the production of active immune checkpoint protein recovered from bacterial cytoplasmic inclusion bodies, being able to obtain an active, and non-glycosylated TIM-3 ectodomain (TIM-3-ECD), which can be used as a tool to better understand the interactions and roles of this immune checkpoint. The TIM-3 refolding was obtained by the association of high pressure and alkaline pH. Results: The purified TIM-3-ECD showed the correct secondary structure and was recognized from anti-TIM-3 structural-dependent antibodies likewise commercial TIM-3-ECD was produced by a mammal cells system. Furthermore, immunofluorescence showed the ability of TIM-3-ECD to bind to the surface of lung cancer A549 cells and to provide an additional boost for the expression of the lymphocyte activation marker CD69 in anti-CD3/CD28 activated human PBMC. Discussion: Taken together these results validated a methodology able to obtain active checkpoint proteins from bacterial inclusion bodies, which will be helpful to further investigate the interactions of this and others not yet explored immune checkpoints.
RESUMO
Introduction: Microbial systems, such as Escherichia coli, as host recombinant expression is the most versatile and the cheapest system for protein production, however, several obstacles still remain, such as recovery of soluble and functional proteins from inclusion bodies, elimination of lipopolysaccharides (LPS) contamination, incomplete synthesis, degradation by proteases, and the lack of post-translational modifications, which becomes even more complex when comes to membrane proteins, because they are difficult not only to produce but also to keep in solution in its active state. T-cell Immunoglobulin and Mucin domain 3 (TIM-3) is a type I transmembrane protein that is predominantly expressed on the surface of T lymphocytes, natural killer (NK) cells, dendritic cells, and macrophages, playing a role as a negative immune checkpoint receptor. TIM-3 comprises a single ectodomain for interaction with immune system soluble and cellular components, a transmembrane domain, and a cytoplasmic tail, responsible for the binding of signaling and scaffolding molecules. TIM-3 pathway holds potential as a therapeutic target for immunotherapy against tumors, autoimmunity, chronic virus infections, and various malignancies, however, many aspects of the biology of this receptor are still incompletely understood, especially regarding its ligands. Methods: Here we overcome, for the first time, the challenge of the production of active immune checkpoint protein recovered from bacterial cytoplasmic inclusion bodies, being able to obtain an active, and non-glycosylated TIM-3 ectodomain (TIM-3-ECD), which can be used as a tool to better understand the interactions and roles of this immune checkpoint. The TIM-3 refolding was obtained by the association of high pressure and alkaline pH. Results: The purified TIM-3-ECD showed the correct secondary structure and was recognized from anti-TIM-3 structural-dependent antibodies likewise commercial TIM-3-ECD was produced by a mammal cells system. Furthermore, immunofluorescence showed the ability of TIM-3-ECD to bind to the surface of lung cancer A549 cells and to provide an additional boost for the expression of the lymphocyte activation marker CD69 in anti-CD3/CD28 activated human PBMC. Discussion: Taken together these results validated a methodology able to obtain active checkpoint proteins from bacterial inclusion bodies, which will be helpful to further investigate the interactions of this and others not yet explored immune checkpoints.
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The aim of this study was to determine the ergogenic effects of metformin in high-intensity exercise, as well as its effects on anaerobic capacity, in healthy and physically active men. Ten subjects (mean (± standard deviation) maximal oxygen uptake (VËO2max ) 38.6 ± 4.5 mL/kg per min) performed the following tests in a cycle ergometer: (i) an incremental test; (ii) six submaximal constant workload tests at 40%-90% (VËO2max ); and (iii) two supramaximal tests (110% (VËO2max ). Metformin (500 mg) or placebo was ingested 60 min before the supramaximal test. There were no significant differences between the placebo and metformin groups in terms of maximum accumulated oxygen deficit (2.8 ± 0.6 vs 3.0 ± 0.8 L, respectively; P = 0.08), lactate concentrations (7.8 ± 2.6 vs 7.5 ± 3.0 mmol/L, respectively; P = 0.75) or O2 consumed in either the last 30 s of exercise (40.4 ± 4.4 vs 39.9 ± 4.0 mL/kg per min, respectively; P = 0.35) or the first 110 s of exercise (29.0 ± 2.5 vs 29.5 ± 3.0 mL/kg per min, respectively; P = 0.42). Time to exhaustion was significantly higher after metformin than placebo ingestion (191 ± 33 vs 167 ± 32 s, respectively; P = 0.001). The fast component of VËO2 recovery was higher in the metformin than placebo group (12.71 vs 12.18 mL/kg per min, respectively; P = 0.025). Metformin improved performance and anaerobic alactic contribution during high-intensity exercise, but had no effect on overall anaerobic capacity in healthy subjects.
Assuntos
Exercício Físico/fisiologia , Voluntários Saudáveis , Metformina/farmacologia , Substâncias para Melhoria do Desempenho/farmacologia , Trifosfato de Adenosina/biossíntese , Anaerobiose/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Adulto JovemRESUMO
Moderate- to high-intensity strength training is recommended for healthy adults. In young subjects, a single session of strength training decreases blood pressure, while heart rate and cardiac work remain elevated afterwards. However, these effects have not been clearly demonstrated in elderly subjects. To investigate this issue, 16 elderly subjects each underwent a Control and an Exercise (3 sets, 8 RM, 9 exercises) session conducted in random order. Haemodynamic variables and heart rate variability were measured before and after the interventions. Systolic blood pressure did not change after the exercise session but did increase after the control session (+8.1±1.6 mm Hg, P≤0.05). Diastolic blood pressure, as well as systemic vascular resistance increased similarly after both sessions. Cardiac output and stroke volume decreased, while heart rate, rate-pressure product and the low- to high-frequency ratio of heart rate variability increased only after the exercise session ( - 0.5±0.1 L/min, - 9.3±2.0 ml,+3.8±1.6 bpm, +579.3±164.1 mmHg.bpm and +0.71±0.34, P≤0.05). Ambulatory blood pressure was similar after both sessions, while heart rate and rate pressure product remained higher after the exercise session for up to 4.5 h. After a single session of strength training, cardiac sympathetic modulation and heart rate remain elevated in elderly subjects, keeping cardiac work elevated for a long period of time.
Assuntos
Envelhecimento/fisiologia , Pressão Sanguínea/fisiologia , Débito Cardíaco/fisiologia , Frequência Cardíaca/fisiologia , Treinamento Resistido , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Determinação da Pressão Arterial , Eletrocardiografia , Exercício Físico/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resistência Vascular/fisiologiaRESUMO
BACKGROUND AND PURPOSE: Bones are widely innervated, suggesting an important role for the sympathetic regulation of bone metabolism, although there are controversial studies. We investigated the effects of propranolol in a model of experimental periodontal disease. EXPERIMENTAL APPROACH: Rats were assigned as follows: animals without ligature; ligated animals receiving vehicle and ligated animals receiving 0.1, 5 or 20 mg·kg(-1) propranolol. After 30 days, haemodynamic parameters were measured by cardiac catheterization. Gingival tissues were removed and assessed for IL-1ß, TNF-α and cross-linked carboxyterminal telopeptides of type I collagen (CTX) by elisa, or intercellular adhesion molecule 1 (ICAM-1), receptor activator of NF-κ B ligand (RANKL) and osteoprotegerin (OPG) by Western blot analysis. Sections from the mandibles were evaluated for bone resorption. Also, we analysed the ability of propranolol to inhibit osteoclastogenesis in vitro. RESULTS: Propranolol at 0.1 and 5 mg·kg(-1) reduced the bone resorption as well as ICAM-1 and RANKL expression. However, only 0.1 mg·kg(-1) reduced IL-1ß, TNF-α and CTX levels as well as increased the expression of OPG, but did not alter any of the haemodynamic parameters. Propranolol also suppressed in vitro osteoclast differentiation and resorptive activity by inhibiting the nuclear factor of activated T cells (NFATc)1 pathway and the expression of tartrate-resistant acid phosphatase (TRAP), cathepsin K and MMP-9. CONCLUSIONS AND IMPLICATIONS: Low doses of propranolol suppress bone resorption by inhibiting RANKL-mediated osteoclastogenesis as well as inflammatory markers without affecting haemodynamic parameters.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Propranolol/administração & dosagem , Fosfatase Ácida/antagonistas & inibidores , Fosfatase Ácida/genética , Perda do Osso Alveolar/prevenção & controle , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Catepsina K/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Colágeno Tipo I/metabolismo , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Gengiva/efeitos dos fármacos , Gengiva/metabolismo , Hemodinâmica/efeitos dos fármacos , Inflamação/prevenção & controle , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Masculino , Metaloproteinase 9 da Matriz/genética , Camundongos , Fatores de Transcrição NFATC/antagonistas & inibidores , Osteoclastos/patologia , Peptídeos/metabolismo , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fosfatase Ácida Resistente a Tartarato , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The aim of the present study was to evaluate the effect of amiodarone on mean arterial pressure (MAP), heart rate (HR), baroreflex, Bezold-Jarisch, and peripheral chemoreflex in normotensive and chronic one-kidney, one-clip (1K1C) hypertensive rats (N = 9 to 11 rats in each group). Amiodarone (50 mg/kg, iv) elicited hypotension and bradycardia in normotensive (-10 +/- 1 mmHg, -57 +/- 6 bpm) and hypertensive rats (-37 +/- 7 mmHg, -39 +/- 19 bpm). The baroreflex index (deltaHR/deltaMAP) was significantly attenuated by amiodarone in both normotensive (-0.61 +/- 0.12 vs -1.47 +/- 0.14 bpm/mmHg for reflex bradycardia and -1.15 +/- 0.19 vs -2.63 +/- 0.26 bpm/mmHg for reflex tachycardia) and hypertensive rats (-0.26 +/- 0.05 vs -0.72 +/- 0.16 bpm/mmHg for reflex bradycardia and -0.92 +/- 0.19 vs -1.51 +/- 0.19 bpm/mmHg for reflex tachycardia). The slope of linear regression from delta pulse interval/deltaMAP was attenuated for both reflex bradycardia and tachycardia in normotensive rats (-0.47 +/- 0.13 vs -0.94 +/- 0.19 ms/mmHg and -0.80 +/- 0.13 vs -1.11 +/- 0.13 ms/mmHg), but only for reflex bradycardia in hypertensive rats (-0.15 +/- 0.02 vs -0.23 +/- 0.3 ms/mmHg). In addition, the MAP and HR responses to the Bezold-Jarisch reflex were 20-30% smaller in amiodarone-treated normotensive or hypertensive rats. The bradycardic response to peripheral chemoreflex activation with intravenous potassium cyanide was also attenuated by amiodarone in both normotensive (-30 +/- 6 vs -49 +/- 8 bpm) and hypertensive rats (-34 +/- 13 vs -42 +/- 10 bpm). On the basis of the well-known electrophysiological effects of amiodarone, the sinus node might be the responsible for the attenuation of the cardiovascular reflexes found in the present study.
Assuntos
Amiodarona/farmacologia , Antiarrítmicos/farmacologia , Células Quimiorreceptoras/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão Renal/fisiopatologia , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Doença Crônica , Eletrofisiologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
The aim of the present study was to evaluate the effect of amiodarone on mean arterial pressure (MAP), heart rate (HR), baroreflex, Bezold-Jarisch, and peripheral chemoreflex in normotensive and chronic one-kidney, one-clip (1K1C) hypertensive rats (N = 9 to 11 rats in each group). Amiodarone (50 mg/kg, iv) elicited hypotension and bradycardia in normotensive (-10 ± 1 mmHg, -57 ± 6 bpm) and hypertensive rats (-37 ± 7 mmHg, -39 ± 19 bpm). The baroreflex index (deltaHR/deltaMAP) was significantly attenuated by amiodarone in both normotensive (-0.61 ± 0.12 vs -1.47 ± 0.14 bpm/mmHg for reflex bradycardia and -1.15 ± 0.19 vs -2.63 ± 0.26 bpm/mmHg for reflex tachycardia) and hypertensive rats (-0.26 ± 0.05 vs -0.72 ± 0.16 bpm/mmHg for reflex bradycardia and -0.92 ± 0.19 vs -1.51 ± 0.19 bpm/mmHg for reflex tachycardia). The slope of linear regression from deltapulse interval/deltaMAP was attenuated for both reflex bradycardia and tachycardia in normotensive rats (-0.47 ± 0.13 vs -0.94 ± 0.19 ms/mmHg and -0.80 ± 0.13 vs -1.11 ± 0.13 ms/mmHg), but only for reflex bradycardia in hypertensive rats (-0.15 ± 0.02 vs -0.23 ± 0.3 ms/mmHg). In addition, the MAP and HR responses to the Bezold-Jarisch reflex were 20-30 percent smaller in amiodarone-treated normotensive or hypertensive rats. The bradycardic response to peripheral chemoreflex activation with intravenous potassium cyanide was also attenuated by amiodarone in both normotensive (-30 ± 6 vs -49 ± 8 bpm) and hypertensive rats (-34 ± 13 vs -42 ± 10 bpm). On the basis of the well-known electrophysiological effects of amiodarone, the sinus node might be the responsible for the attenuation of the cardiovascular reflexes found in the present study.
Assuntos
Animais , Masculino , Ratos , Amiodarona/farmacologia , Antiarrítmicos/farmacologia , Células Quimiorreceptoras , Hemodinâmica/efeitos dos fármacos , Hipertensão Renal/fisiopatologia , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Doença Crônica , Eletrofisiologia , Frequência Cardíaca/efeitos dos fármacos , Ratos WistarRESUMO
The aim of the present study was to investigate the effects of converting enzyme inhibition by captopril on ECG parameters in aged rats. Four-month-old male rats received captopril dissolved in tap water (0.5 mg/l) or tap water for 2 or 20 months. At the end of treatment, under anesthesia, RR and PR interval, P wave and QRS duration, QT and corrected QT interval were measured in all animals. On the following day, chronic ECG (lead II) recordings were performed to quantify supraventricular (SVPB) or ventricular premature beats (VPB). After sacrifice, the hearts were removed and weighed. RR interval was similar in young and untreated aged rats, but significantly larger in aged rats treated with captopril. P wave and QRS length did not differ among groups. PR interval was significantly larger in old than in young rats and was not affected by captopril. Corrected QT interval was larger in aged than in young rats (117 +/- 4 vs 64 +/- 6 ms, P<0.05) and was reduced by captopril (71 +/- 6 ms, P<0.05). VPB were absent in young rats and highly frequent in untreated old animals (8.4 +/- 3.0/30 min). Captopril significantly reduced VPB in old rats (0.3 +/- 0.1/30 min, P<0.05). The cardiac hypertrophy found in untreated aged rats was prevented by captopril (3.44 +/- 0.14 vs 3.07 +/- 0.10 mg/g, P<0.05). The beneficial effects of angiotensin converting enzyme inhibition on the rat heart during the aging process are remarkable.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Envelhecimento , Análise de Variância , Animais , Masculino , Ratos , Ratos WistarRESUMO
The aim of the present study was to investigate the effects of converting enzyme inhibition by captopril on ECG parameters in aged rats. Four-month-old male rats received captopril dissolved in tap water (0.5 mg/l) or tap water for 2 or 20 months. At the end of treatment, under anesthesia, RR and PR interval, P wave and QRS duration, QT and corrected QT interval were measured in all animals. On the following day, chronic ECG (lead II) recordings were performed to quantify supraventricular (SVPB) or ventricular premature beats (VPB). After sacrifice, the hearts were removed and weighed. RR interval was similar in young and untreated aged rats, but significantly larger in aged rats treated with captopril. P wave and QRS length did not differ among groups. PR interval was significantly larger in old than in young rats and was not affected by captopril. Corrected QT interval was larger in aged than in young rats (117 ± 4 vs 64 ± 6 ms, P<0.05) and was reduced by captopril (71 ± 6 ms, P<0.05). VPB were absent in young rats and highly frequent in untreated old animals (8.4 ± 3.0/30 min). Captopril significantly reduced VPB in old rats (0.3 ± 0.1/30 min, P<0.05). The cardiac hypertrophy found in untreated aged rats was prevented by captopril (3.44 ± 0.14 vs 3.07 ± 0.10 mg/g, P<0.05). The beneficial effects of angiotensin converting enzyme inhibition on the rat heart during the aging process are remarkable
Assuntos
Animais , Masculino , Ratos , Inibidores da Enzima Conversora de Angiotensina , Captopril , Eletrocardiografia , Frequência Cardíaca , Envelhecimento , Análise de Variância , Ratos WistarRESUMO
The antihypertensive effect of amiodarone was investigated in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The SHR and WKY were treated with amiodarone (1 mg/mL PO) or tap water (control) for 20 weeks. The indirect arterial pressure (AP) was monitored weekly using the tail-cuff method. At the end of the 20th week, the direct AP was measured, and the systolic AP and pulse interval time series were submitted to autoregressive spectral analysis. In addition, cardiac baroreflex sensitivity and left ventricular weight were evaluated as well. The indirect AP was reduced 1 week after the beginning of amiodarone treatment. The direct mean AP and pulse interval were, respectively, 135+/-8 mm Hg and 191+/-3 ms in SHR treated with amiodarone (187+/-8 mm Hg and 156+/-7 ms in control SHR, P<0.05) and 87+/-3 mm Hg and 207+/-8 ms in WKY treated with amiodarone (105+/-8 mm Hg and 174+/-4 ms in control WKY, P<0.05). In SHR treated with amiodarone, the low-frequency oscillations of AP were lower (8.5+/-1.2 mm Hg(2) versus 14.4+/-2.9 mm Hg(2) in control SHR, P<0.05), whereas the reflex bradycardia was higher (0.84+/-0.12 ms/mm Hg versus 0.32+/-0.22 ms/mm Hg in control SHR, P<0.05). The left ventricle weight was also smaller in SHR treated with amiodarone (2.94+/-0.12 mg/g versus 3.45+/-0.24 mg/g in control SHR, P<0.05). In WKY, amiodarone induced similar changes as in SHR, except for a lack of effect in the left ventricle weight. These data indicate that amiodarone has an antihypertensive action in SHR that is associated with a reduction in vasomotor sympathetic modulation, an increase in vagal cardiac baroreflex sensitivity, and a decrease in cardiac hypertrophy.
Assuntos
Amiodarona/farmacologia , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/fisiopatologia , Bradicardia/prevenção & controle , Diástole , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Masculino , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Reflexo/efeitos dos fármacos , Sístole , Fatores de Tempo , Vasoconstritores/farmacologia , Vasodilatadores/farmacologiaRESUMO
Alterations of the autonomic reflex control of the cardiovasclar system have been demonstrated in clinical and animal models of insulin-dependent diabetes mellitus. Established neuroaxonal dystrophy is considered the neuropathological hallmark of chronic experimental diabetes. However, the afferent arm of the arterial baroreflex, that is, the carotid sinus nerve and the aortic depressor nerve, has received much less attention in studies dealing with this physiopathological model. The attenuation of the pressure response to bilateral carotid occlusion in conscious rats indicates a derangement of the baroreflex, probably involving an alteration of the carotid sinus nerve. There is histological evidence obtained from adult spontaneous insulin-dependent diabetic rats (strain BB/S) of a carotid sinus nerve with signs of axonal swelling and intramyelinic edema, suggesting diabetic neuropathy. The study of aortic baroreceptor activity in anesthetized rats with short- and long-term streptozotocin diabetes by means of cross-spectral analysis of baroreceptor activity versus arterial pressure revealed a dysfunction in the afferent arm of the baroreflex even during a short period of diabetes. The morphology of the aortic depressor nerve of streptozotocin-diabetic rats indicated axonal atrophy by visual analysis remarkably at the distal segments of the nerves. This finding was confirmed by morphometric study of the myelinated fibers. In conclusion, although studies of the arterial baroreceptors related to experimental diabetes are scanty in the literature, there is electrophysiological and histological evidence demonstrating that the carotid sinus and the aortic depressor nerves are abnormal in this experimental model.
Assuntos
Artérias/inervação , Diabetes Mellitus Experimental/fisiopatologia , Pressorreceptores/fisiopatologia , Animais , Aorta/inervação , Barorreflexo/fisiologia , Seio Carotídeo/inervação , Sistema Nervoso/fisiopatologiaRESUMO
The present study evaluated the possible changes in the autonomic control of heart rate in the hypertensive model induced by the inhibition of nitric oxide synthase. Rats were treated with N(G)-nitro-L-arginine methyl ester (L-NAME group) in the drinking water during 7 days, whereas control groups were treated with tap water (control group) or with the N(G)-nitro-D-arginine methyl ester (D-NAME group), an inactive isomer of the L-NAME molecule. The L-NAME group developed hypertension and tachycardia. The sequential blockade of the autonomic influences with propranolol and methylatropine indicated that the intrinsic heart rate did not differ among groups and revealed a sympathetic overactivity in the control of heart rate in the L-NAME group. The spectral density power of heart rate, calculated using fast-Fourier transformation, indicated a reduced variability in the low-frequency band (0.20-0.60 Hz) for the L-NAME group. The baroreflex sensitivity was also attenuated in these animals when compared with the normotensive control or D-NAME group. Overall, these data indicate cardiac sympathetic overactivity associated with a decreased baroreflex sensitivity in L-NAME hypertensive rats.
Assuntos
Barorreflexo/fisiologia , Coração/inervação , Hipertensão/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Anti-Hipertensivos/farmacologia , Derivados da Atropina/farmacologia , Barorreflexo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Análise de Fourier , Coração/fisiologia , Frequência Cardíaca/fisiologia , Hipertensão/induzido quimicamente , Masculino , Miocárdio/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Ácido Nítrico/metabolismo , Parassimpatolíticos/farmacologia , Propranolol/farmacologia , Ratos , Ratos Wistar , Sistema Nervoso Simpático/efeitos dos fármacos , Taquicardia/induzido quimicamente , Taquicardia/fisiopatologiaRESUMO
BACKGROUND: Chronic diabetes is associated with alterations in autonomic modulation of the cardiovascular system. Although the rat has been used extensively in studies of experimental diabetes, there have been no reports on the changes in autonomic modulation of the cardiovascular function in chronic diabetic rats. OBJECTIVE: To examine chronic diabetic rats to determine the autonomic modulation of arterial pressure and heart rate variabilities in the time and frequency domain. MATERIALS AND METHODS: Diabetes was induced in rats by a single injection of streptozotocin, and 30 min of pulsatile arterial pressure was recorded in conscious rats, 5, 10-20 days and 12-18 weeks after the streptozotocin injection. Control rats were injected with vehicle. Beat-by-beat systolic arterial pressure and heart rate were obtained from pulsatile pressure. The spectral density powers of systolic arterial pressure and heart rate were calculated using fast Fourier transformation, and integrated in low-(0.015-0.25 Hz), mid- (0.25-0.75 Hz) and high- (0.75-3.0 Hz) frequency bands. The standard deviations of systolic arterial pressure and heart rate were also calculated. RESULTS: Basal systolic arterial pressure and heart rate were reduced in diabetic animals studied 10-20 days and 12-18 weeks after the streptozotocin injection. The standard deviations of systolic arterial pressure and heart rate were also reduced in the chronically diabetic animals. Diabetes reduced low- and mid-frequency variability but not the high-frequency variability of systolic arterial pressure. The low-frequency variability, but not the mid-frequency variability, of the heart rate was also reduced, while the high-frequency variability of the heart rate was reduced in the more chronically diabetic rats. CONCLUSION: Our findings that the mid-frequency band variability of arterial pressure was reduced in diabetic patients suggest that sympathetic modulation of the cardiovascular system is impaired, corroborating other studies in such patients using this and other approaches.
Assuntos
Pressão Sanguínea , Diabetes Mellitus Experimental/fisiopatologia , Frequência Cardíaca , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Masculino , Ratos , Ratos Wistar , Estreptozocina , Sistema Nervoso Simpático/fisiopatologiaRESUMO
We investigated the acute and chronic effects of converting enzyme inhibitors (captopril or enalapril) and of angiotensin II receptor blockade (DuP 753) on rapid (30-minute) baroreceptor resetting elicited by a prompt and sustained hypertensive response provoked by aortic constriction. Pressure-nerve activity curves, pressure at 50% of maximal baroreceptor activity, baroreceptor gain (slope of the curve), and systolic threshold pressure for baroreceptor activation were determined as indexes of baroreceptor function. A slight fall in mean arterial pressure after acute treatment with the converting enzyme inhibitor or DuP 753 was accompanied by a partial leftward curve shift, which is associated with a partial threshold shift and increase in gain. A maintained hypertensive stimulus caused a partial rightward curve shift and partial (49% to 56%) threshold shift to hypertensive levels in both acutely treated and control rats. The hypertensive stimulus provoked a partial rightward curve shift and complete (88% to 94%) threshold shift to hypertensive levels in chronically treated rats. The effect of enalapril on baroreceptor function was unaltered by the bradykinin antagonist Hoe 140. These data demonstrate that chronic inhibition of converting enzyme or blockade of angiotensin II receptors facilitates rapid resetting of the baroreceptors to hypertensive levels caused by partial aortic constriction without a change in baroreceptor sensitivity.
Assuntos
Angiotensina II/antagonistas & inibidores , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Enalapril/farmacologia , Hipertensão/fisiopatologia , Imidazóis/farmacologia , Pressorreceptores/efeitos dos fármacos , Tetrazóis/farmacologia , Angiotensina I/farmacologia , Angiotensina II/farmacologia , Animais , Aorta/inervação , Bradicinina/farmacologia , Losartan , Masculino , Pressorreceptores/fisiologia , Pressorreceptores/fisiopatologia , Ratos , Ratos Wistar , Valores de Referência , Análise de RegressãoRESUMO
We investigated the role of nitric oxide on rapid (25- and 40-minute) baroreceptor resetting during the onset of acute hypertension in rats treated with NG-nitro-L-arginine, an inhibitor of nitric oxide synthesis, and methylene blue, an inhibitor of guanylate cyclase. The effect of treatment with glibenclamide, an ATP-dependent K+ channel blocker, was also investigated. Arterial hypertension was provoked in a ramp progression by the drug NG-nitro-L-arginine alone or in association with aortic coarctation. Whole aortic nerve activity and carotid pressure were recorded in the anesthetized rats. The extent of rapid resetting was evaluated by means of the ratio (delta Systolic Threshold Pressure/delta Control Diastolic Pressure) x 100 as well as by the extent of displacement of the pressure-nerve activity curve defined by the ratio (delta Mean Arterial Pressure at 50% of maximum activity/delta Mean Arterial Pressure) x 100. All groups gave the same increase in mean arterial pressure at 25 and 40 minutes after the onset of hypertension. A greater extent of resetting to hypertensive levels was observed in the treated groups compared with coarctation alone. At 40 minutes after the onset of hypertension, the coarctation and nitro-L-arginine groups exhibited a further increase in the extent of resetting. The rats submitted to glibenclamide plus coarctation presented a slight but significant decrease in gain. These findings suggest that an active L-arginine-nitric oxide-cyclic GMP pathway blunts rapid resetting during the onset of hypertension. In addition, they also indicate that ATP-dependent K+ channels can also modulate rapid resetting of the baroreceptors to hypertensive levels.