RESUMO
BACKGROUND: Our group has previously shown that short-term treatment (48â¯h) with esmolol reduces left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). However, we do not know the mechanism that explain this effect. The aim of this study was to assess the role that the subcellular organelle phenotype plays in early cardiac reverse after short-term treatment with esmolol. METHODS: 14-Month-old male SHRs were randomly assigned to receive esmolol (300⯵g/kg/min) (SHR-E) or vehicle (SHR). Age-matched male Wistar-Kyoto rats (WKY) served as controls. After 48â¯h of treatment, an ultrastructural analysis of heart tissue (left ventricle) was performed. We studied cardiomyocyte ultrastructural remodeling of subcellular organelles by electronic microcopy in all groups. RESULTS: SHR group showed significant morphometric and stereological changes in mitochondria and subcellular organelles (cytoplasm and nucleus, myofibril structure, mitochondria structure, Z-Disk, intercalated disk, T-system and cystern), and also changes in the extracellular matrix (collagen) with respect to WKY group. Esmolol significantly improved the morphology and stereology mitochondrial, reduced the organelle phenotype abnormalities but no produced changes in the extracellular matrix with respect to SHR group. Interesantly, parameters of mitochondria (regularity factor, ellipsoidal form factor and density of volume), and all parameters of subcellular organelles returned to the normality in SHR-E. CONCLUSION: Our results show that left ventricular hypertrophy reversal after short-term treatment with esmolol is associated with reversal of subcellular organelle phenotype.
Assuntos
Hipertrofia Ventricular Esquerda/tratamento farmacológico , Miocárdio/patologia , Miocárdio/ultraestrutura , Organelas/patologia , Organelas/ultraestrutura , Propanolaminas/farmacologia , Animais , Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Dronedarone is recommended for the treatment of atrial fibrillation. However, we do not know its effect on vascular remodeling. This study was designed to assess whether dronedarone has the potential to improve the intramyocardial artery remodeling induced by chronic hypertension. Ten-month-old male spontaneously hypertensive rats (SHR) were randomly assigned to receive dronedarone (100 mg/kg) or vehicle. Age-matched male Wistar-Kyoto rats served as controls. After 14 days of treatment, we studied the structure (geometry and fibrosis) of the intramyocardial artery using histological analysis. Nitric oxide (NO) in plasma was analyzed. In the untreated SHR, we observed a significant increase in external diameter, lumen diameter, wall width, cross-sectional area, and collagen volume density, as was expected in the experimental model. Dronedarone induced a significant decrease in wall width, cross-sectional area, and collagen volume density in SHR-D in comparison with untreated SHR. The values obtained in SHR-D were similar in the WKY control group. We found significantly higher NO levels in plasma in SHR-D than in untreated SHR. Dronedarone improves the intramyocardial artery remodeling induced by chronic hypertension in SHR through increased nitric oxide bioavailability.
Assuntos
Vasos Coronários , Dronedarona/farmacologia , Hipertensão , Óxido Nítrico/sangue , Remodelação Vascular/efeitos dos fármacos , Animais , Doença Crônica , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Hipertensão/fisiopatologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
BACKGROUND: Left ventricular hypertrophy (LVH) has been associated with oxidative stress, although not with the protein thiolation index (PTI). This study explored the potential use of PTI as a biomarker of oxidative stress in patients with LVH. METHODS: We recruited 70 consecutive patients (n = 35 LVH and n = 35 non-LVH) based on an echocardiography study in our institution (left ventricular mass indexed to body surface area). Plasma levels of both S-thiolated protein and total thiols were measured as biomarkers of oxidative stress by spectrophotometry, and PTI was calculated as the molar ratio between S-thiolated proteins and the total thiol concentration. RESULTS: Values for plasma S-thiolated proteins were higher in patients with LVH than in the control group (P = 0.01). There were no differences in total thiols between the LVH group and the control group. Finally, PTI was higher in patients with LVH than in the control group (P = 0.001). The area under the ROC curve was 0.75 (95% CI, 0.63-0.86; P<0.001), sensitivity was 70.6%, and specificity was 68.6%, thus suggesting that PTI could be used to screen for LVH. A multivariable logistic regression model showed a positive association (P = 0.02) between PTI and LVH (OR = 1.24 [95% CI, 1.03-1.49]) independently of gender (OR = 3.39 [95% CI, 0.60-18.91]), age (OR = 1.03 [95% CI, 0.96-1.10]), smoking (OR = 5.15 [95% CI, 0.51-51.44]), glucose (OR = 0.99 [95% CI, 0.97-1.01]), systolic arterial pressure (OR = 1.10 [CI 1.03-1.17]), diastolic arterial pressure (OR = 0.94 [CI 0.87-1.02]), dyslipidemia (OR = 1.46 [95% CI, 0.25-8.55]), estimated glomerular filtration rate (OR = 0.98 [95% CI, 0.96-1.01]), body mass index (OR = 1.03 [95% CI, 0.90-1.10]), and valvular and/or coronary disease (OR = 5.27 [95% CI, 1.02-27.21]). CONCLUSIONS: The present study suggests that PTI could be a new biomarker of oxidative stress in patients with LVH.
Assuntos
Proteínas Sanguíneas/metabolismo , Hipertrofia Ventricular Esquerda/diagnóstico , Compostos de Sulfidrila/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse OxidativoRESUMO
BACKGROUND AND AIMS: Dronedarone is a new multichannel-blocking antiarrhythmic for the treatment of patients with atrial fibrillation. Our group has demonstrated that dronedarone produces regression of cardiac remodeling; however, its effect on the remodeling of the elastic arteries has not yet been reported. We aim to assess the effects of dronedarone on the regression of thoracic aortic remodeling in spontaneously hypertensive rats (SHRs). METHOD: Ten-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where the animals received dronedarone treatment (100 mg/kg), to a control group (SHR) where rats were given vehicle, or to a group (SHR-A) where they were given amiodarone. A fourth group of normotensive control rats (Wistar-Kyoto rats, WKY) was also added. After two weeks of treatment, we studied the structure, the elastic fiber content of the thoracic aorta using histological techniques and confocal microscopy, and the vascular mechanical properties using an organ bath and isometric tension analysis. A mass spectrometric determination of symmetric dimethylarginine (SDMA) concentrations was performed. RESULTS: SHR group developed the classic remodeling expected from the experimental model: outward hypertrophic remodeling, increased elastic fiber content and wall stiffness. However, the SHR-D group showed statistically significantly lower values for aortic tunica media thickness, wall to lumen ratio, external diameter, cross-sectional area, volume density of the elastic fibers, wall stiffness, and aortic SDMA concentration when compared to the SHR group. These parameters were similar in the SHR and SHR-A groups. Interestingly, the values for tunica media thickness, volume density of the elastic fibers, wall stiffness, and SDMA concentration obtained from the SHR-D group were similar to those measured in the WKY group. CONCLUSION: These results suggest that dronedarone improves the structure and passive mechanical properties of the thoracic aorta in hypertensive rats, and that this protective effect could be associated with a reduction in the concentration of aortic SDMA.
Assuntos
Aorta Torácica/metabolismo , Arginina/análogos & derivados , Dronedarona/farmacologia , Hipertensão/tratamento farmacológico , Remodelação Vascular/efeitos dos fármacos , Animais , Aorta Torácica/patologia , Arginina/metabolismo , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Microscopia Confocal , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Our group previously demonstrated that dronedarone induces regression of left ventricular hypertrophy in spontaneously hypertensive rats (SHRs). We assessed changes in vascular remodeling and oxidative stress following short-term use of this agent. The coronary artery was isolated from 10-month-old male SHRs treated with 100 mg kg-1 dronedarone once daily for 14 days (SHR-D group), and age-matched untreated SHRs were used as hypertensive controls. We analyzed the geometry and composition of the artery and constructed dose-response curves for acetylcholine and serotonin (5-HT). We calculated a global score (OXY-SCORE) from plasma biomarkers of oxidative status: carbonyl levels, thiol levels, reduced glutathione levels, total antioxidant capacity, and superoxide anion scavenging activity. Finally, we analyzed asymmetric dimethylarginine (ADMA) concentrations in plasma. Dronedarone significantly decreased wall thickness (medial and adventitial layer thickness and cell count) and the cross-sectional area of the artery. Dronedarone significantly improved endothelium-dependent relaxation and reduced the contraction induced by 5-HT. The OXY-SCORE was negative in the SHR model group (suggesting an enhanced oxidative status) and was positive in the SHR-D group (suggesting enhanced antioxidant defense). Dronedarone significantly decreased the concentrations of ADMA. We conclude that dronedarone improves coronary artery remodeling in SHRs. The better global antioxidant status after treatment with dronedarone and decreased plasma ADMA levels could contribute to the cardiovascular protective effect of dronedarone.
Assuntos
Antioxidantes/metabolismo , Vasos Coronários/efeitos dos fármacos , Dronedarona/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Arginina/análogos & derivados , Arginina/sangue , Vasos Coronários/patologia , Vasos Coronários/fisiologia , Masculino , Óxido Nítrico/fisiologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vasoconstrição/efeitos dos fármacosRESUMO
Our group has previously demonstrated that short-term treatment with esmolol reduces left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). The present study aimed to assess the molecular mechanisms related to this effect. Fourteen-month-old male SHRs were treated intravenously with saline as vehicle (SHR) or esmolol (SHR-E) (300 µg/kg/min). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 hours of treatment, the hearts were harvested and left ventricular tissue was separated and processed for Western blot analysis to determine the levels of Akt, NF-κB, NFATc4, Creb1, Serca2a, Erk1/2, and Sapk/Jnk. Biomarkers of oxidative stress, such as catalase, protein carbonyls, total thiols, and total antioxidant capacity were evaluated. Esmolol reversed the levels of p-NFATc4, p-Akt, and p-NF-κB in SHRs to the phospholevels of these proteins in WKY rats without modifying p-Erk1/2, p-Sapk/Jnk, p-Creb1, or Serca2a in SHR. Compared with SHR, esmolol increased catalase activity and reduced protein carbonyls without modifying total thiols or total antioxidant capacity. Short-term treatment with esmolol reverses LVH in aged SHRs by downregulation of Akt/NF-κB and NFATc4 activity. Esmolol treatment also increases catalase activity and reduces oxidative stress in SHRs with LVH.
Assuntos
Envelhecimento/metabolismo , Hipertrofia Ventricular Esquerda/tratamento farmacológico , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Propanolaminas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antioxidantes/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Catalase/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Propanolaminas/administração & dosagem , Propanolaminas/farmacologia , Carbonilação Proteica/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Sístole/efeitos dos fármacos , Fatores de TempoRESUMO
BACKGROUND AND AIMS: Left ventricular hypertrophy (LVH) in hypertension is associated with a greater risk of sustained supraventricular/atrial arrhythmias. Dronedarone is an antiarrhythmic agent that was recently approved for the treatment of atrial fibrillation. However, its effect on early regression of LVH has not been reported. We tested the hypothesis that short-term administration of dronedarone induces early regression of LVH in spontaneously hypertensive rats (SHRs). METHODS: Ten-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where animals received dronedarone treatment (100 mg/kg) for a period of 14 days, or to a control group (SHR) where rats were given vehicle. A third group with normotensive control rats (WKY) was also added. At the end of the treatment with dronedarone we studied the cardiac anatomy and function in all the rats using transthoracic echocardiogram, cardiac metabolism using the PET/CT study (2-deoxy-2[18F]fluoro-D-glucose) and cardiac structure by histological analysis of myocyte size and collagen content. RESULTS: The hypertensive vehicle treated SHR rats developed the classic cardiac pattern of hypertensive cardiomyopathy as expected for the experimental model, with increases in left ventricular wall thickness, a metabolic shift towards an increase in glucose use and increases in myocyte and collagen content. However, the SHR-D rats showed statistically significant lower values in comparison to SHR group for septal wall thickness, posterior wall thickness, ventricular mass, glucose myocardial uptake, size of left ventricular cardiomyocytes and collagen content. All these values obtained in SHR-D rats were similar to the values measured in the normotensive WKY control group. CONCLUSION: The results suggest by three alternative and complementary ways (analysis of anatomy and cardiac function, metabolism and histological structure) that dronedarone has the potential to reverse the LVH induced by arterial hypertension in the SHR model of compensated ventricular hypertrophy.
Assuntos
Amiodarona/análogos & derivados , Cardiopatias/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Amiodarona/administração & dosagem , Animais , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/efeitos dos fármacos , Dronedarona , Cardiopatias/diagnóstico por imagem , Cardiopatias/fisiopatologia , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ratos , Ratos Endogâmicos SHR/fisiologiaRESUMO
BACKGROUND: Spontaneously hypertensive rats (SHR) serve as a model of genetic hypertension. Adverse remodeling of a coronary artery has been reported in SHR. This model is used to study new therapies in regression vascular remodeling. However, no data are available that show remodeling of the intramyocardial branch of the obtuse marginal artery in 10-month-old SHR. This study was designed to assess remodeling (changes in vascular structure and fibrosis) of this coronary artery. METHODS AND RESULTS: The study was performed on 10-month-old male SHR (n=7) and normotensive control Wistar Kyoto rats (WKY) (n=7). Using histology, we show that the external diameter, lumen diameter, wall width, and cross-sectional area of the intramyocardial artery were significantly greater in SHR than in WKY. The wall-to-lumen ratio was similar in SHR and WKY. The collagen volume density of the intramyocardial artery in SHR was significantly greater than in WKY. CONCLUSIONS: Our results show hypertrophic outward remodeling in the intramyocardial branch of the obtuse marginal artery of the left ventricle in SHR. This artery can serve as a new vascular bed from adult SHR to study novel therapies in regression coronary artery remodeling.
Assuntos
Vasos Coronários/patologia , Hipertensão/patologia , Miocárdio/patologia , Remodelação Vascular , Animais , Modelos Animais de Doenças , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia/etiologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Esmolol produces early regression of left ventricular hypertrophy and improves coronary artery remodeling, although the impact of short-term treatment with this beta-blocker on remodeling in large arteries has not yet been studied. We hypothesized that even a short (48h) course of esmolol might alter remodeling of the aorta in the spontaneously hypertensive rat (SHR). Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=8) or esmolol (SHR-E, n=8) (300µg/kg/min). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=8) served as controls. After 48h, we studied the structure, volume density of elastic fibers, and passive mechanical properties of the aorta. Determination of asymmetrical dimethylarginine concentrations and total protein carbonyls in the aorta were analyzed. Esmolol significantly attenuated abnormal aortic wall thickness, cross-sectional area, wall-to-lumen ratio, volume density of elastic fibers, and wall stiffness. The protective effect of esmolol could be related to a decrease in asymmetrical dimethylarginine levels after down-regulation by oxidative stress. These findings could play a key role in the selection of antihypertensive therapy in patients with hypertension and aortic remodeling.
Assuntos
Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Arginina/análogos & derivados , Regulação para Baixo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Propanolaminas/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Aorta Torácica/fisiopatologia , Arginina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Resistência à Tração/efeitos dos fármacosRESUMO
[This corrects the article DOI: 10.1155/2015/898373.].
RESUMO
Our preclinical study demonstrated that esmolol produces early regression of left ventricular hypertrophy in arterial hypertension. The aim of this study was to assess the effects of short-term esmolol therapy on the regression of left anterior descending artery remodeling in spontaneously hypertensive rats (SHRs), and to determine whether the asymmetric dimethylarginine (ADMA)/dimethylarginine dimethylaminohydrolase (DDAH) pathway, a regulator of nitric oxide (NO) bioavailability, accounted for this regression. Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=15) or esmolol (SHR-E, n=20) (300 µg kg-1 min-1). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=15) served as controls. SHRs were also treated with nitroglycerin (SHR-N, n=5). After 48 h, the left anterior descending artery structure and morphology were assessed, and dose-response curves for 5-hydroxytryptamine (5-HT, 10-9-3 × 10-5 mol l-1) were constructed. ADMA concentrations in plasma and left ventricle and DDAH activity in tissue were analyzed. Wall thickness and cross-sectional area were significantly lower after treatment with esmolol in SHR-E than in SHR. Media thickness and smooth muscle cell count were lower in SHR-E than in SHR. Esmolol induced a significant reduction in adventitial cell count in SHR-E. The area under the concentration-response curves was significantly higher in SHR than in SHR-E, as were the esmolol normalized coronary artery contracting responses to 5-HT. We found significantly lower ADMA levels and significantly higher DDAH activity in the ventricle in SHR-E than in SHR. The protective effect of esmolol on the regression of left anterior descending artery remodeling may be related to the reduction in ADMA levels.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Amidoidrolases/metabolismo , Arginina/análogos & derivados , Vasos Coronários/efeitos dos fármacos , Hipertensão/metabolismo , Propanolaminas/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Arginina/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Relação Dose-Resposta a Droga , Hipertensão/patologia , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Serotonina/farmacologia , Remodelação Vascular/fisiologiaRESUMO
Hypertensive left ventricular hypertrophy (LVH) is a maladaptive response to chronic pressure overload and a strong independent risk factor for cardiovascular disease. Regression of LVH is associated with improved prognosis. Regression of LVH with antihypertensive therapy (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, and diuretics) has been reported, although only after long-term treatment. Asymmetrical dimethylarginine (ADMA), the most potent endogenous NO synthase inhibitor, is emerging as an important cardiovascular risk factor in patients with arterial hypertension and LVH, and dimethylarginine dimethylaminohydrolase (DDAH) is the mechanism that most frequently leads to accumulation of ADMA (plasma ADMA is cleared in small part by renal excretion, although the bulk of ADMA is degraded by DDAH). Left ventricular mass is strongly modulated by the NO system. As an important inhibitor of the bioavailability of NO, ADMA is an underlying mechanism of LVH. Beta-blockers can induce regression of LVH and reduced plasma ADMA levels. Oxidative stress is increased in patients with LVH, and this in turn increases generation of ADMA. In a previous preclinical study of spontaneously hypertensive rats, we found that short-term treatment (48 h) with esmolol reverses early LVH, increases the bioavailability of NO, and improves antioxidant status in plasma. Therefore, we propose that the ADMA/DDAH/NO pathway could modulate early regression of LVH with esmolol.
Assuntos
Hipertrofia Ventricular Esquerda/tratamento farmacológico , Propanolaminas/uso terapêutico , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Amidoidrolases/metabolismo , Animais , Anti-Hipertensivos/uso terapêutico , Arginina/análogos & derivados , Arginina/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Modelos Cardiovasculares , Óxido Nítrico/metabolismo , Ratos , Ratos Endogâmicos SHR , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/fisiologiaRESUMO
The aim of this study was to assess the effect of sevoflurane and propofol on organ blood flow in a porcine model with a left ventricular assist device (LVAD). Ten healthy minipigs were divided into 2 groups (5 per group) according to the anesthetic received (sevoflurane or propofol). A Biomedicus centrifugal pump was implanted. Organ blood flow (measured using colored microspheres), markers of tissue injury, and hemodynamic parameters were assessed at baseline (pump off) and after 30 minutes of partial support. Blood flow was significantly higher in the brain (both frontal lobes), heart (both ventricles), and liver after 30 minutes in the sevoflurane group, although no significant differences were recorded for the lung, kidney, or ileum. Serum levels of alanine aminotransferase and total bilirubin were significantly higher after 30 minutes in the propofol group, although no significant differences were detected between the groups for other parameters of liver function, kidney function, or lactic acid levels. The hemodynamic parameters were similar in both groups. We demonstrated that, compared with propofol, sevoflurane increases blood flow in the brain, liver, and heart after implantation of an LVAD under conditions of partial support.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Coração Auxiliar , Éteres Metílicos/administração & dosagem , Propofol/administração & dosagem , Animais , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Sevoflurano , Suínos , Porco Miniatura , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
The aim of this study was to assess the effects of short-term esmolol therapy on coronary artery structure and function and plasma oxidative stress in spontaneously hypertensive rats (SHR). For this purpose, 14-month-old male SHR were treated for 48 hours with esmolol (SHR-E, 300 µ g/kg/min). Age-matched untreated male SHR and Wistar Kyoto rats (WKY) were used as hypertensive and normotensive controls, respectively. At the end of intervention we performed a histological study to analyze coronary artery wall width (WW), wall-to-lumen ratio (W/L), and media cross-sectional area (MCSA). Dose-response curves for acetylcholine (ACh) and sodium nitroprusside were constructed. We also assessed several plasma oxidative stress biomarkers, namely, superoxide scavenging activity (SOSA), nitrites, and total antioxidant capacity (TAC). We observed a significant reduction in WW (P < 0.001), W/L (P < 0.05), and MCSA (P < 0.01) and improved endothelium-dependent relaxation (AUC(SHR-E) = 201.2 ± 33 versus AUC(SHR) = 97.5 ± 21, P < 0.05) in SHR-E compared with untreated SHR; no differences were observed for WW, MCSA, and endothelium-dependent relaxation by ACh at higher concentrations (10(-6) to 10(-4) mol/l) for SHR-E with respect to WKY. SOSA (P < 0.001) and nitrite (P < 0.01) values were significantly higher in SHR-E than in untreated SHR; however, TAC did not increase after treatment with esmolol. Esmolol improves early coronary artery remodeling in SHR.
Assuntos
Vasos Coronários/efeitos dos fármacos , Hipertensão/metabolismo , Óxido Nítrico/metabolismo , Propanolaminas/farmacologia , Superóxido Dismutase/metabolismo , Animais , Antioxidantes/análise , Disponibilidade Biológica , Vasos Coronários/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Epiphyseal cartilage is hyaline cartilage tissue with a gelatinous texture, and it is responsible for the longitudinal growth of the long bones in birds and mammals. It is located between the epiphysis and the diaphysis. Epiphyseal cartilage also is called a growth plate or physis. It is protected by three bone components: the epiphysis, the bone bar of the perichondrial ring and the metaphysis. The epiphysis, which lies over the epiphyseal cartilage in the form a cupola, contains a juxtaposed bone plate that is near the epiphyseal cartilage and is in direct contact with the epiphyseal side of the epiphyseal cartilage. The germinal zone corresponds to a group of cells called chondrocytes. These chondrocytes belong to a group of chondral cells, which are distributed in rows and columns; this architecture is commonly known as a growth plate. The growth plate is responsible for endochondral bone growth. The aim of this study was to elucidate the causal relationship between the juxtaposed bone plate and epiphyseal cartilage in mammals. Our hypothesis is that cells from the germinal zone of the epiphyseal side of the epiphyseal cartilage are involved in forming a second ossification front that is responsible for the origin of the juxtaposed bone plate. We report the following: (a) The juxtaposed bone plate has a morphology and function that differs from that of the epiphyseal trabeculae; (b) on the epiphyseal edge of the epiphyseal cartilage, a new ossification front starts on the chondrocytes of the germinal area, which forms the juxtaposed bone plate. This ossification front is formed by chondrocytes from the germinal zone through a process of mineralisation and ossification, and (c) the process of mineralisation and ossification has a certain morphological analogy to the process of ossification in the metaphyseal cartilage of amphibians and differs from the endochondral ossification process in the metaphyseal side of the growth plate. The close relationship between the juxtaposed bone plate and the epiphyseal cartilage, in which the chondrocytes that migrate from the germinal area play an important role in the mineralisation and ossification process of the juxtaposed bone plate, supports the hypothesis of a new ossification front in the epiphyseal layer of the epiphyseal plate. This hypothesis has several implications: (a) epiphyseal cartilage is a morphological entity with two different ossification fronts and two different functions, (b) epiphyseal cartilage may be a morphological structure with three parts: perichondrial ring, metaphyseal ossification front or growth plate, and epiphyseal ossification front, (c) all disease (traumatic or dysplastic) that affects some of these parts can have an impact on the morphology of the epiphyseal region of the bone, (d) there is a certain analogy between metaphyseal cartilage in amphibians and mammalian epiphyseal cartilage, although the former is not responsible for bone growth, (e) comparative histological and anatomy studies are also warranted, to shed light on the phylogenetic study of epiphyseal cartilage throughout the changes that occur in the animal species.
Assuntos
Desenvolvimento Ósseo/fisiologia , Lâmina de Crescimento/anatomia & histologia , Lâmina de Crescimento/fisiologia , Modelos Biológicos , Osteogênese/fisiologia , Animais , Lâmina de Crescimento/cirurgia , Técnicas Histológicas , Humanos , Microcirurgia , RatosRESUMO
Certain ß-adrenergic blockers have proven useful in the regression of ventricular remodeling when administered as long-term treatment. However, early regression of left ventricular hypertrophy (LVH) has not been reported, following short-term administration of these drugs. We tested the hypothesis that short-term administration of the cardioselective ß-blocker esmolol induces early regression of LVH in spontaneously hypertensive rats (SHR). Fourteen-month-old male SHRs were treated i.v. with vehicle (SHR) or esmolol (SHR-E) (300 µg kg(-1) min(-1)). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 h, left ventricular morphology and function were assessed using M-mode echocardiograms (left ventricular mass index (LVMI), ejection fraction and transmitral Doppler (early-to-atrial filling velocity ratio (E/A), E-wave deceleration time (Edec time)). The standardized uptake value (SUV) was applied to evaluate FDG (2-deoxy-2[18F]fluoro-D-glucose) uptake by the heart using PET/CT. Left ventricular subendocardial and subepicardial biopsies were taken to analyze changes in cross-sectional area (CSA) of left ventricular cardiomyocytes and the fibrosis was expressed as collagen volume fraction (CVF). LVMI was lower in SHR-E with respect to SHR (P=0.009). There were no significant differences in EF, E/A ratio or Edec time in SHR-E compared with SHR (P=0.17, 0.55 and P=0.80, respectively). PET acquisitions in SHR-E showed lower (18)F-FDG uptake than SHR (P=0.003). Interestingly, there were no significant differences in SUV in either SHR-E or WKY (P=0.63). CSA in subendocardial and subepicardial regions was minor in SHR-E with respect to SHR (P<0.001), and there were no significant differences in CVF between both groups. Esmolol reverses early LVH in the SHR model of stable compensated ventricular hypertrophy. This is the first study to associate early regression of LVH with administration of a short-term ß-blocker.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Propanolaminas/administração & dosagem , Animais , Avaliação Pré-Clínica de Medicamentos , Fluordesoxiglucose F18 , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , UltrassonografiaRESUMO
BACKGROUND: An anatomo-functional system has been described for the normal hip of some young mammals. This system includes the ligamentum teres, the transverse acetabular ligament, and the meniscoid of the hip. PURPOSE: This report analyzes morphologic changes in the anatomo-functional system of young rats in an experimental model of hip luxation, and on the initial pathodynamics of luxation produced experimentally. METHODS: Hyperextension of the left knee was induced in 58 young rats through fixation of the tibia and femur with Kirschner wire. Radiographic, macroscopic, and microscopic parameters were analyzed for 3 study periods (group 1: 4 d, group 2: 1 wk, group 3: 2 wk), and macroscopic parameters were studied in a late group (group 4: 6 wk). RESULTS: Breaks in the Shenton line were observed from group 1 (subluxation) onward (luxation). Hypertrophy of the round and transverse acetabular ligaments of the acetabulum and meniscoid, progressive elevation of the meniscoid, and fibrosis of the fibrofatty (pulvinar) tissue occurred from group 1 onward. Radiographic and morphometric studies showed triplane innominate bone deformation (anterior bending, lateral tilt, and rotation of the ischium), which resulted in decreased joint space. As time progressed, the increase in these injuries was accompanied by morphologic changes in the acetabulum, posterosuperior displacement and reorientation of the acetabulum and extrusion of the femoral head. CONCLUSIONS: Under the conditions of this study, the temporospatial morphologic changes in the acetabulum due to injury of the anatomo-functional system, and the triplane pelvic deformity in the initial period of the injury, produced femoral head extrusion of the acetabulum. RELEVANT SYMPTOMS: These disorders may help us understand the pathogenic and clinical phenomena that appear in early stages of hip luxation disease.
Assuntos
Acetábulo/patologia , Cabeça do Fêmur/patologia , Luxação do Quadril/fisiopatologia , Articulação do Joelho/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Fêmur , Hipertrofia , Ratos , Ratos Sprague-Dawley , Tíbia , Fatores de TempoRESUMO
Liver growth factor (LGF) is an endogenous albumin-bilirubin complex with antihypertensive effects in spontaneously hypertensive rats (SHR). We assessed the actions of LGF treatment on SHR mesenteric resistance and intramyocardial arteries (MRA and IMA, respectively), heart, and vascular smooth muscle cells (VSMC). SHR and Wistar-Kyoto (WKY) rats treated with vehicle or LGF (4.5 µg LGF/rat, 4 ip injections over 12 days) were used. Intra-arterial blood pressure was measured in anesthetized rats. The heart was weighted and paraffin-embedded. Proliferation, ploidy, and fibronectin deposition were studied in carotid artery-derived VSMC by immunocytochemistry. In MRA, we assessed: 1) geometry and mechanics by pressure myography; 2) function by wire myography; 3) collagen by sirius red staining and polarized light microscopy, and 4) elastin, cell density, nitric oxide (NO), and superoxide anion by confocal microscopy. Heart sections were used to assess cell density and collagen content in IMA. Left ventricular hypertrophy (LVH) regression was assessed by echocardiography. LGF reduced blood pressure only in SHR. LGF in vitro or as treatment normalized the alterations in proliferation and fibronectin in SHR-derived VSMC with no effect on WKY cells. In MRA, LGF treatment normalized collagen, elastin, and VSMC content and passive mechanical properties. In addition, it improved NO availability through reduction of superoxide anion. In IMA, LGF treatment normalized perivascular collagen and VSMC density, improving the wall-to-lumen ratio. Paired experiments demonstrated a partial regression of SHR LVH by LGF treatment. The effective cardiovascular antifibrotic and regenerative actions of LGF support its potential in the treatment of hypertension and its complications.
Assuntos
Anti-Hipertensivos/administração & dosagem , Bilirrubina/administração & dosagem , Vasos Coronários/efeitos dos fármacos , Matriz Extracelular/metabolismo , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Artérias Mesentéricas/efeitos dos fármacos , Albumina Sérica/administração & dosagem , Resistência Vascular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Análise de Variância , Animais , Pressão Sanguínea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Elastina/metabolismo , Fibronectinas/metabolismo , Fibrose , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Imuno-Histoquímica , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/patologia , Artérias Mesentéricas/fisiopatologia , Microscopia Confocal , Microscopia de Polarização , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Miografia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Albumina Sérica Humana , Superóxidos/metabolismo , Ultrassonografia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Liver regeneration after partial hepatectomy (PHx) is a complex process that is regulated by hemodynamic changes, the modulation of cytokines and growth factors, and the activation of immediate early transcription factors that lead to a round of hepatocyte mitosis. Among the factors involved, the pituitary hormone prolactin (PRL) has been shown to induce a hepatotrophic response after partial hepatectomy similar to that caused by phorbol esters; and in isolated hepatocytes PRL triggers a mitogenic response. However, it is becoming clear that PRL exerts a dual role acting in proliferation and differentiation processes. In this work, we have assessed the role of PRL in the early stages of liver regeneration in rats. To this end, three groups of rats were compared: Sham operated, regenerant and regenerant with PRL i.p. administration. Results show that PRL administration prior to partial hepatectomy caused an increase in the binding activity of several transcription factors involved in cell proliferation: AP-1, c-Jun and STAT-3, and in liver-specific differentiation and maintenance of energetic metabolism: CEBPalpha, HNF-1, HNF-4 at early time points and at later time points HNF-3. Hepatic sections show that PRL administration increases the number of proliferating cells within 5 h post-partial hepatectomy. The mRNA of the angiogenic and survival factors VEGF and HIF-1alpha, was also induced by PRL treatment. Data indicate that PRL triggers, either directly or indirectly, an acceleration of liver regeneration, preserving liver function and fulfilling a hepatoprotective role. J. Cell. Physiol. 219: 626-633, 2009. (c) 2009 Wiley-Liss, Inc.
Assuntos
Regeneração Hepática/fisiologia , Prolactina/fisiologia , Animais , Sequência de Bases , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Proliferação de Células/efeitos dos fármacos , Primers do DNA/genética , Feminino , Hepatectomia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/fisiologia , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/genética , Prolactina/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fatores de Tempo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Standard noninvasive imaging techniques applied to joints provide gross morphological features, insufficient for assessing histological detail. On the other hand, biopsying is invasive, time consuming, and may involve unwanted processing artifacts. Near-infrared reflectance confocal microscopy is a technique that allows serial, high-resolution optical sectioning through intact tissues without employing exogenous fluorescent stains. The aim of this work was to evaluate the potential utility of near-infrared reflectance confocal microscopy for providing immediate histological information on meniscus, articular cartilage, epiphyseal plate, bone, muscle, and tendon. Images from near-infrared reflectance confocal microscopy were compared with mirror routine histology sections. Characteristic architectural features were readily visualized in the three dimensions of space. Additionally, the use of experimental contrast agents highlighted the localization of nuclei. Limitations include penetration depth and minor optical artifacts. In conclusion, near-infrared reflectance confocal microscopy is a useful technique for immediate, nondestructive, serial "virtual" sectioning through intact tissues, being thus a potential adjunct to current imaging techniques in orthopedics.