ABSTRACT
Abstract Background: Trimetazidine (TMZ) is an anti-ischemic drug. In spite of its protective effects on cardiovascular system, there is no scientific study on the usefulness of TMZ treatment for prolonged QT interval and cardiac hypertrophy induced by diabetes. Objectives: To evaluate the effects of TMZ on QT interval prolongation and cardiac hypertrophy in the diabetic rats. Methods: Twenty-four male Sprague-Dawley rats (200-250 g) were randomly assigned into three groups (n = 8) by simple random sampling method. Control (C), diabetic (D), and diabetic administrated with TMZ at 10 mg/kg (T10). TMZ was administrated for 8 weeks. The echocardiogram was recorded before isolating the hearts and transfer to a Langendorff apparatus. Hemodynamic parameters, QT and corrected QT interval (QTc) intervals, heart rate and antioxidant enzymes were measured. The hypertrophy index was calculated. The results were evaluated by one-way ANOVA and paired t-test using SPSS (version 16) and p < 0.05 was regarded as significant. Results: The diabetic rats significantly indicated increased hypertrophy, QT and QTc intervals and decreased Left ventricular systolic pressure (LVSP), Left ventricular developed pressure (LVDP), rate pressure product (RPP), Max dp/dt, and min dp/dt (±dp/dt max), heart rate, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase in the heart. Treatment with TMZ in the diabetic animals was significantly improved these parameters in comparison to the untreated diabetic group. Conclusions: TMZ improves QTc interval prolongation and cardiac hypertrophy in diabetes.
Resumo Fundamento: A trimetazidina (TMZ) é uma droga anti-isquêmica. Apesar de seus efeitos protetores sobre o sistema cardiovascular, não há estudos científicos sobre a utilidade do tratamento com TMZ para o intervalo QT prolongado e a hipertrofia cardíaca induzida pelo diabetes. Objetivo: Avaliar os efeitos da TMZ no prolongamento do intervalo QT e na hipertrofia cardíaca em ratos diabéticos. Métodos: Vinte e quatro ratos machos Sprague-Dawley (200-250 g) foram distribuídos aleatoriamente em três grupos (n = 8) pelo método de amostragem aleatória simples. Controle (C), diabético (D) e diabético administrado com TMZ a 10 mg/kg (T10). A TMZ foi administrada por 8 semanas. O ecocardiograma foi registrado antes de isolar os corações e transferir para um aparelho de Langendorff. Foram medidos os parâmetros hemodinâmicos, intervalo QT e intervalo QT corrigido (QTc), frequência cardíaca e enzimas antioxidantes. O índice de hipertrofia foi calculado. Os resultados foram avaliados pelo one-way ANOVA e pelo teste t pareado pelo SPSS (versão 16) e p < 0,05 foi considerado significativo. Resultados: Os ratos diabéticos indicaram hipertrofia aumentada, intervalos QT e QTc e diminuição da pressão sistólica no ventrículo esquerdo (PSVE), pressão desenvolvida no ventrículo esquerdo (PDVE), duplo produto (DP), Max dp/dt e min dp/dt (± dp/dt max), frequência cardíaca, superóxido dismutase (SOD), glutationa peroxidase (GPx) e catalase no coração. O tratamento com TMZ nos animais diabéticos melhorou significativamente esses parâmetros em comparação com o grupo diabético não tratado. Conclusões: A TMZ melhora o prolongamento do intervalo QTc e a hipertrofia cardíaca no diabetes.
Subject(s)
Animals , Male , Trimetazidine/pharmacology , Long QT Syndrome/drug therapy , Cardiomegaly/drug therapy , Protective Agents/pharmacology , Diabetes Complications/drug therapy , Superoxide Dismutase/analysis , Time Factors , Long QT Syndrome/enzymology , Long QT Syndrome/physiopathology , Echocardiography , Catalase/analysis , Random Allocation , Reproducibility of Results , Rats, Sprague-Dawley , Cardiomegaly/enzymology , Cardiomegaly/etiology , Cardiomegaly/physiopathology , Diabetes Complications/enzymology , Diabetes Complications/physiopathology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/physiopathology , Glutathione Peroxidase/analysis , Hemodynamics/drug effectsABSTRACT
Resumen: Objetivo: Determinar algunos mecanismos moleculares por los cuales la activación de ROCK cardíaca post infarto del miocardio (IAM) participa en el remodelado y en deterioro de la función sistólica. Métodos: Determinación simultánea de niveles de proteínas blanco de ROCK cardíaca, de función sistólica in vivo del ventrículo izquierdo (VI) y de fibrosis e hipertrofia cardíaca en ratas con IAM en condiciones de inhibición de ROCK con fasudil. Resultados : Siete días post IAM la masa ventricular relativa aumentó significativamente en un 30% en el grupo MI y se redujo con fasudil. La disfunción sistólica VI mejoró significativamente con fasudil mientras que la activación de ROCK cardíaca se redujo a niveles del grupo control. El inhibidor de ROCK también redujo significativamente los niveles cardíacos elevados de las isoformas ROCK1 y ROCK2, de MHC-β y del colágeno miocárdico. En el grupo con IAM aumentaron significativamente los niveles de fosforilación de ERK 42 y ERK 44 (en 2 veces y en 63%, respectivamente), mientras que en el grupo IAM tratado con fasudil estos niveles fueron similares a los del grupo control. El IAM aumentó significativamente los niveles fosforilados del factor de transcripción GATA-4, que se normalizaron con el inhibidor de ROCK. Conclusiones: La disfunción sistólica post IAM se asoció fuertemente con la activación del ROCK cardíaca y con la fosforilación de proteínas río abajo de ROCK que promueven remodelado cardíaco como β-MHC y la vía ERK / GATA-4.
Abstracts: Objective: to determine some molecular mechanisms by which cardiac ROCK activation after myocardial infarction (MI) intervene in cardiac systolic function decline and remodeling. Methods: simultaneous measurement of different cardiac ROCK target proteins levels, in vivo left ventricular (LV) systolic function, myocardial fibrosis, and hypertrophy in rats with MI under ROCK inhibition with fasudil were performed. Results: seven days after MI the relative ventricular mass increased significantly by 30% in the MI groupand was reduced with fasudil. LV systolic dysfunction improved significantly with fasudil whereas at the same time cardiac ROCK activation was reduced to sham levels. The ROCK inhibitor also reduced increased cardiac levels of both ROCK1 and ROCK2 isoforms, β-MHC levels and myocardial collagen volume fraction decline. MI significantly increased phosphorylation levels of ERK 42 and ERK 44 by 2-fold and 63% respectively whereas in the fasudil-treated MI group these levels were similar to those in the sham group. MI significantly increased phosphorylated levels of the transcription factor GATA-4 which were normalyzed by the ROCK inhibitor. Conclusion: LV systolic dysfunction after MI was strongly associated to cardiac ROCK activation and subsequent phosphorylation of ROCK target proteins that promote ventricular remodeling, such as β-MHC and the ERK/GATA-4 pathway. ROCK inhibition with fasudil significantly improved systolic function, diminished myocardial fibrosis, and normalized β-MHC and ERK/GATA-4 phosphorylation levels.
Subject(s)
Animals , Rats , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , Protein Kinase Inhibitors/pharmacology , rho-Associated Kinases/antagonists & inhibitors , Myocardial Infarction/drug therapy , Organ Size/drug effects , Phosphorylation , Blotting, Western , Ventricular Function, Left/drug effects , Rats, Sprague-Dawley , Cardiomegaly/drug therapy , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Ventricular Remodeling/drug effects , Disease Models, Animal , Myocardial Infarction/enzymologySubject(s)
Adrenergic beta-Antagonists/administration & dosage , Angiotensin II/antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Cardiomegaly/drug therapy , Drug Therapy, Combination , Humans , Myocardium/pathology , Receptors, Angiotensin/antagonists & inhibitors , Renin-Angiotensin System/drug effectsABSTRACT
OBJECTIVE - Angiotensin-converting enzyme inhibitors (ACEIs) have gained importance in preventing or attenuating the process of ventricular remodeling after myocardial infarction. The significance of infarct size in regard to the response to ACEIs, however, is controversial. This study aimed to analyze the effects of lisinopril on mortality rate, cardiac function, degree of cardiac hypertrophy and fibrosis in rats with different in. There was no statistical difference between the groups with small and large infarcts in regard to myocardial concentration of hydroxyproline. In small infarcts, the treatment attenuated the heart dysfunction characterized by lower levels of blood pressure and lower values of the first derivative of pressure and of the negative derivative of pressure. The degree of hypertrophy was also attenuated in small infarcts. In regard to large infarcts, no differences between the groups were observed. CONCLUSION - Treatment with the ACEIs had no effect on mortality rate and on the amount of fibrosis. The protective effect of lisinopril on heart function and on the degree of hypertrophy could only be detected in small infarcts
Subject(s)
Animals , Male , Rats , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Lisinopril/pharmacology , Myocardial Infarction/physiopathology , Severity of Illness Index , Ventricular Remodeling/drug effects , Cardiomegaly/drug therapy , Fibrosis/drug therapy , Hydroxyproline/analysis , Myocardial Infarction/complications , Myocardial Infarction/mortality , Rats, WistarABSTRACT
Cardiac hypertrophy that accompanies hypertension seems to be a phenomenon of multifactorial origin whose development does not seem to depend on an increased pressure load alone, but also on local growth factores and cardioadrenergic activity. The aim of the present study was to determine if sympathetic renal denervation and its effects on arterial pressure level can prevent cardiac hypertrophy and if it can also delay the onset and attenuate the severity of deoxycorticosterone acetate (DOCA)-salt hypertension. DOCA-salt treatment was initiated in rats seven days after uninephrectomy and contralateral renal denervation or sham renal denervation. DOCA (15 mg/kg, sc) or vehicle (soybean oil, 0.25 ml per animal) was administered twice a week for two weeks. Rats treated with DOCA or vehicle (control) were provided drinking water containing 1 percent NaCl and 0.03 percent KCl. At the end of the treatment period, mean arterial pressure (MAP) and heart rate measurements were made in conscious animals. Under ether anesthesia, the heart was removed and the right and left ventricles (including the septum) were separated and weighed. DOCA-salt treatment produced a significant increase in left ventricular weight/body weight (LVW/BW) ratio (2.44 + 0.09 mg/g) and right ventricular weight/body weight (RVW/BW) ratio (0.53 + 0.01 mg/g) compared to control (1.92 + 0.04 and 0.48 + 0.01 mg/g, respectively) rats. MAP was significantly higher (39 percent) in DOCA-salt rats. Renal denervation prevented (P>0.05) the development of hypertension in DOCA-salt rats but did not prevent the increase in LVW/BW (2.27 + 0.03 mg/g) and RVW/BW (0.52 + 0.01 mg/g). We have shown that the increase in arterial pressure level is not responsible for cardiac hypertrophy, which may be more related to other events associated with DOCA-salt hypertension, such as an increase in cardiac sympathetic activity.
Subject(s)
Rats , Animals , Male , Blood Pressure/drug effects , Cardiomegaly , Desoxycorticosterone/therapeutic use , Kidney/innervation , Kidney/surgery , Sodium Chloride, Dietary , Cardiomegaly/drug therapy , Cardiomegaly/etiology , Heart Rate/drug effects , Organ Size , Rats, WistarABSTRACT
Com a introduçao dos inibidores da enzima conversora da angiotensina (IECAs) - peptídios que inibem a atividade da cinase e têm potente açao inibitória sobre a conversao da angiotensina I em angiotensina II -, o tratamento da ICC e da HA evoluiu consideravelmente. A eficácia clínica destas drogas estimulou o interesse internacional em pesquisar o sistema renina-angiotensina, possibilitando assim a descoberta do sistema renina-angiotensina tecidual, a presença de receptores específicos para angiotensina II neste sistema e de antagonistas nao-peptídicos seletivos para estes receptores.
Subject(s)
Humans , Animals , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Heart Failure/drug therapy , Arterial Pressure , Renin-Angiotensin System/physiology , Angiotensin II/antagonists & inhibitors , Angiotensin II/physiology , Antihypertensive Agents/therapeutic use , Cardiomegaly/drug therapy , Receptors, Angiotensin/drug effects , Renin-Angiotensin System/drug effectsSubject(s)
Humans , Antihypertensive Agents/pharmacokinetics , Hypertension/drug therapy , Cardiomegaly/drug therapy , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Endothelial Growth Factors/physiology , Hemodynamics/physiology , Sympathetic Nervous System , Sympathetic Nervous System/physiopathologyABSTRACT
Objetivo: Avaliar os efeitos do maleato de enalapril na regressão da hipertrofia ventricular esquerda (EVE) associada a hipertensão arterial. Casuística e Métodos: Quinze pacientes masculinos, idades entre 45 e 65 anos, média 56, com hipertensão arterial essencial leve ou moderada (pressão arterial diastólica, PAD, entre 90 e 114 mmHg) e HVE ao exame ecocardiográfico. A administração de enalapril iniciou-se com dose diária única de 20 mg, aumentada até o máximo de 40 mg, se a PAD permanecesse acima de 90 mmHg e não houvessem reações adversas...
Purpose: To evaluate the effects of enalapril maleate on the regression of left ventricular hypertrophy (LVH) associated to hypertension. Patients and Methods: Fifteen male, age between 45 and 65 years (mean age = 56 y) with diagnosis of mild-to-moderate essential hypertension (> diastolic blood pressure [DBP] < between 90 and 114 mmHg) and LHV at the echocardiogram. The administration of enalapril maleate was initiated with a 20 mg daily dosage and titrated up to a maximum of 40 mg daily, whenever DBP was maintained above 90 mmHg and no adverse experience occurred...
Subject(s)
Humans , Male , Middle Aged , Enalapril/therapeutic use , Hypertension/drug therapy , Cardiomegaly/drug therapy , Blood Pressure/drug effects , Enalapril/administration & dosage , Clinical Trials as TopicABSTRACT
En 104 hipertensos esenciales leves y moderados se midieron mediante ecocardiografía los cambios inducidos en la masa ventricular izquierda (MV) por el tratamiento con monodrogas durante por lo menos 12 meses. Los pacientes (p) fueron clasificados en 4 grupos (G). G1: 40p tratados con atenolol, G2: 32p tratados con maleato de enalapril, G3: 22p tratados cocn nifedipina, G4: grupo control, 10 en los primeros 3 grupos, pero no se modificó en el G4. La frecuencia cardíaca se redujo significativamente solo en el G1. El peso corporal no varió. Los pacientes fueron subclasificados de acuerdo a que su MV fuese normal (N, MV, < 120 g/m2 en hombres) o aumentada (H). Hubo una reducción significativa de la MV en todos los grupos H. La relación MV/volumen de fin de diastole del ventrículo izquierdo (M/V) cayó en todos los grupos H. Hubo una correlación pequeña, aunque significativa entre la PA vbasal y la MV. La regresión de la MV fue mayor en los ventrículos hipertróficos, sin que se produjesen cambios significativos en a fracción de acortamiento. En base a estos resultados parecería razonable elegir para el tratamiento las drogas antihipertensivas que reduzcan la MV
Subject(s)
Humans , Male , Female , Atenolol/therapeutic use , Blood Pressure/drug effects , Cardiomegaly/drug therapy , Enalapril/therapeutic use , Hypertension/drug therapy , Cardiomegaly/etiology , Control Groups , Drug Administration Schedule , Hypertension/complicationsABSTRACT
Resultados previos mostraron que la hipertrofia cardíaca (HC) y la respuesta contráctil al Isoproterenol (I) en el modelo 2R Ic, se normalizagba tres semanas sdespués del descenso de la presión arterial (PA) por el declipado de la arteria renal. En el presente trabajo se estudió el efecto de la Alfa Metidopa (aMD) sobre la PA, HC y la respuesta al I. Con ese propósito, a 43 ratas macho Wistar, de 280 gramos, se las dividió en: a) Grupo Control (C) (n = 24). Luego de tres semanas de control de PA, a 17 de ellas se les administró aMD per os a la dosis de 100 mg/kg/día durante 21 días (C alta). b) Grupo clip (K) (n = 19), a los que se les colocó un clip de plata en la arteria renal izquierda. Luego de tres semanas de hipertensión a (n = 9) (K alfa) se les administró aMD en forma similar a C Alfa. La respuesta al I se evaluó a los 21 a C y K y a los 42 días a C alfa y K alfa. A tal fin, previa anestesia se canularon la carótida, la arteria y vena femorales y se registró la frecuencia cardíaca (FC), la presión arterial media (PAM), la presión sistólica y diastólica de ventrículo izquierdo y la DP/DT + MAX en condiciones basales, y luego de dosis unicas crecientes de I. Al finalizar la experiencia se determinó el peso biventricular (PC) y se normalizó por el peso corporal (pc). La PA aumentó en K (p < 0,05): 179 ñ 2,3 vs C 125 ñ 2,9 y con aMD descendió: C alfa 111 + 2,5 y K alfa 151,7 ñ 6 (p < 0,05). EIPC (g) con aMD fue menor en C alfa (p < 0,05) 0,69 ñ 0,04 vs 0,78 ñ 0,05 y en K alfa...
Subject(s)
Rats , Animals , Male , Blood Pressure/drug effects , Cardiomegaly/drug therapy , Hypertension, Renovascular/physiopathology , Isoproterenol/pharmacology , Methyldopa/pharmacology , Heart Rate , Organ Size/drug effects , Rats, WistarABSTRACT
Foi avaliada a complacência e a hipertrofia ventricular em 24 pacientes com hipertensäo arterial (HA) leve ou moderada (pressäo sistólica entre 160 a 180 e diastólica entre 90 e 120 Hg). Doze pacientes tomaram diariamente 100 mg de atenolol e 25 mg de clortalidona (grupo A) e 12 tomaram 100 mg de metoprolol e 12,5 mg de hidroclorotiazida (grupo B). O estudo foi duplo-cego, precedido de 4 semanas com placebo e com avaliaçäo, ecocardiográfica (eco) e laboratorial após 24 e 36 semanas de tratamento. As drogas foram bem toleradas e com normalizaçäo das pressöes sistólicas e diastólica em todos, embora com diminuiçäo maior da pressäo sistólica (p < 0,01) no grupo A. A bradicardizaçäo foi semelhante nos 2 grupos. As seguintes medidas eco diminuíram significativamente: espessura diastólica da parede posterior (EDPP), espessura diastólica do septo (EDS), índice de massa do ventrículo esquerdo (IMVE), estresse sistólico (ES) e complacência ventricular medida pelo tempo de relaxamento isovolumétrico do ventrículo esquerdo (TRIV). Graças às duas avaliaçöes, com 24 e com 36 semanas de tratamento, pôde-se observar que a normalizaçäo foi contínua e progressiva, maior na fase final do que na intermediária. Este fato parece confirmar a necessidade de um tratamento prolongado e continuado da HA, para se obter o melhor resultado. Por outro lado, os índices de funçäo sistólica näo se alteraram(fraçäo de ejeçäo, fraçäo de encurtamento do diâmetro interno do VE). Houve discreto aumento dos valores sangüíneos de ácido úrico, glicose e colesterol e pequena diminuiçäo do potássio, com ambas associaçöes de drogas e quase sempre dentro dos limites da normalidade