RESUMO
INTRODUCTION: The function of endoplasmic reticulum (ER), a Ca2+ storage compartment and site of protein folding, is altered by disruption of intracellular homeostasis. Misfolded proteins accumulated in the ER lead to ER stress (ERS), unfolded protein response (UPR) activation and ER Ca2+ loss. Myocardial stunning is a temporary contractile dysfunction, which occurs after brief ischemic periods with minimal or no cell death, being oxidative stress and Ca2+ overload potential underlying mechanisms. Myocardial stunning induces ERS response with negatively impact on the post-ischemic mechanical performance through an unknown mechanism. AIMS: In this study, we explored whether ER Ca2+ efflux through the translocon, a major Ca2+ leak channel, contributes to Ca2+ mishandling and the consequent contractile abnormalities of the stunned myocardium. METHODS: Mechanical performance, cytosolic Ca2+, UPR markers and oxidative state were evaluated in perfused rat/mouse hearts subjected to a brief ischemia followed by reperfusion (I/R) in absence or presence of the translocon inhibitor, emetine (1 µM), comparing its effects with those of the chaperones TUDCA (30 µM) and 4-PBA (3 mM). RESULTS: Emetine treatment precluded the I/R-induced increase in UPR signaling markers and improved the contractile recovery together with a remarkable attenuation in myocardial stiffness when compared to I/R hearts with no drug. This alleviation of I/R-induced mechanical abnormalities was more effective than that obtained with the chemical chaperones, TUDCA and 4-PBA. Moreover, emetine treatment produced a striking improvement in diastolic Ca2+ handling with a partial recovery of the I/R-induced oxidative stress. CONCLUSION: Blocking ER Ca2+ store depletion via translocon suppressed ER stress and improved mechanical performance and diastolic Ca2+ handling of stunned myocardium. Modulation of translocon permeability emerges as a therapeutic approach to face dysfunctional consequences of the I/R injury.
Assuntos
Cálcio/metabolismo , Emetina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Contração Miocárdica , Miocárdio Atordoado , Canais de Translocação SEC/antagonistas & inibidores , Resposta a Proteínas não Dobradas , Animais , Sinalização do Cálcio , Camundongos , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Miocárdio Atordoado/tratamento farmacológico , Miocárdio Atordoado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/fisiologiaRESUMO
AIM: Myocardial ischaemia/reperfusion (I/R) produces structural and functional alterations depending on the duration of ischaemia. Brief ischaemia followed by reperfusion causes reversible contractile dysfunction (stunned heart) but long-lasting ischaemia followed by reperfusion can result in irreversible injury with cell death. Events during I/R can alter endoplasmic reticulum (ER) function leading to the accumulation of unfolded/misfolded proteins. The resulting ER stress induces activation of several signal transduction pathways, known as unfolded protein response (UPR). Experimental evidence shows that UPR contributes to cell death in irreversible I/R injury; however, there is still uncertainty for its occurrence in the stunned myocardium. This study investigated the ER stress response and its functional impact on the post-ischaemic cardiac performance of the stunned heart. METHODS: Perfused rat hearts were subjected to 20 minutes of ischaemia followed by 30 minutes of reperfusion. UPR markers were evaluated by qRT-PCR and western blot. Post-ischaemic mechanical recovery was measured in absence and presence of two chemical chaperones: tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA). RESULTS: Analysis of mRNA and protein levels of various ER stress effectors demonstrated that different UPR signalling cascades, involving both pro-survival and pro-apoptotic pathways, are activated. Inhibition of the UPR with chemical chaperones improved the post-ischaemic recovery of cardiac mechanical function without affecting the I/R-induced increase in oxidative stress. CONCLUSION: Our results suggest that prevention of ER stress by chemical chaperones could be a therapeutic tool to limit deterioration of the contractile function in clinical settings in which the phenomenon of myocardial stunning is present.
Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio Atordoado/tratamento farmacológico , Miocárdio/metabolismo , Fenilbutiratos/farmacologia , Ácido Tauroquenodesoxicólico/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Colagogos e Coleréticos/farmacologia , Modelos Animais de Doenças , Proteínas de Choque Térmico/metabolismo , Masculino , Miocárdio Atordoado/etiologia , Miocárdio Atordoado/patologia , Miocárdio/patologia , Ratos , Ratos Wistar , Transdução de Sinais , Resposta a Proteínas não DobradasRESUMO
Isolated rabbit hearts were exposed to ischemia (I; 15 min) and reperfusion (R; 5-30 min) in a model of stunned myocardium. I/R decreased left-ventricle O(2) consumption (46%) and malate-glutamate-supported mitochondrial state 3 respiration (32%). Activity of complex I was 28% lower after I/R. The pattern observed for the decline in complex I activity was also observed for the reduction in mitochondrial nitric oxide synthase (mtNOS) biochemical (28%) and functional (50%) activities, in accordance with the reported physical and functional interactions between complex I and mtNOS. Malate-glutamate-supported state 4 H(2)O(2) production was increased by 78% after I/R. Rabbit heart Mn-SOD concentration in the mitochondrial matrix (7.4±0.7 µM) was not modified by I/R. Mitochondrial phospholipid oxidation products were increased by 42%, whereas protein oxidation was only slightly increased. I/R produced a marked (70%) enhancement in tyrosine nitration of the mitochondrial proteins. Adenosine attenuated postischemic ventricular dysfunction and protected the heart from the declines in O(2) consumption and in complex I and mtNOS activities and from the enhancement of mitochondrial phospholipid oxidation. Rabbit myocardial stunning is associated with a condition of dysfunctional mitochondria named "complex I syndrome." The beneficial effect of adenosine could be attributed to a better regulation of intracellular cardiomyocyte Ca(2+) concentration.
Assuntos
Adenosina/administração & dosagem , Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias Cardíacas/metabolismo , Miocárdio Atordoado/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Respiração Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ventrículos do Coração/patologia , Peroxidação de Lipídeos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/patologia , Miocárdio Atordoado/tratamento farmacológico , Miocárdio Atordoado/patologia , Óxido Nítrico Sintase/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Coelhos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Superóxido Dismutase/metabolismoRESUMO
AIM: To examine the effects of an Ilex paraguariensis (Ip) extract on postischemic alterations derived from 20 min of global ischemia and 30 min of reperfusion. METHODS: Isolated rat hearts were treated 10 min before ischemia and the first 10 min of reperfusion with Ip 30 microg/ml. In other hearts, chelerythrine (1 microM), a protein kinase C blocker, or l(G)-nitro l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor, were administered prior to Ip infusion. Left ventricular developed pressure (LVDP), +dP/dt(max), -dP/dt(max), and left ventricular end diastolic pressure (LVEDP) were used to assess myocardial function. Thiobarbituric acid reactive substances (TBARS) were measured. RESULTS: Ip treatment produced an improvement of postichemic recovery (LVDP=96+/-8%; +dP/dt(max)=95+/-10%; -dP/dt(max)=90+/-12% vs. 57+/-6%, 53+/-6% and 57+/-8%, respectively, in untreated hearts) and an attenuation of the increase of LVEDP and TBARS content. Chelerythrine did not modify and l-NAME abolished the protection induced by Ip. CONCLUSIONS: These data are the first demonstration that Ip extract attenuates the myocardial dysfunction provoked by ischemia and reperfusion and that this cardioprotection involves a diminution of oxidative damage through a nitric oxide-dependent mechanism.
Assuntos
Cardiotônicos/farmacologia , Ilex paraguariensis/química , Miocárdio Atordoado/tratamento farmacológico , Fitoterapia , Extratos Vegetais/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Alcaloides , Animais , Benzofenantridinas , Cardiotônicos/uso terapêutico , Técnicas In Vitro , Contração Miocárdica/efeitos dos fármacos , Miocárdio Atordoado/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II , Fenantridinas/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Inibidores da Agregação Plaquetária/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Objetivo: Evaluar la acción de la trimetazidina en el deterioro de la función sistólica que se produce en el miocardio tras una isquemia única y prolongada. Métodos: Se analizaron 13 perros mestizos, de uno u otro sexo, asignados al azar a tratamiento oral con trimetazidina (6 perros) o placebo (7 perros) durante 7 días. Se realizó un protocolo de isquemia bajo anestesia consistente en una obstrucción completa de la arteria coronaria descendente anterior de 15 minutos de duración, seguida de 60 minutos de reperfusión. Las variables analizadas durante la obstrucción y la reperfusión fueron: Frecuencia cardíaca (FC), presión ventricular izquierda (PVI), dP/dt y las curvas de función regional de la zona isquémica y de una zona testigo (longitud telediastólica, telesistólica y fracción de acortamiento). Resultados: Las variables hemodinámicas (FC, PVI y dP/dt), no presentaron diferencias significativas entre ambos grupos, con poca variabilidad de sus valores respecto a los basales durante la isquemia-reperfusión. La fracción de acortamiento de la zona isquémica experimentó una disminución estadísticamente significativa durante la obstrucción coronaria en ambas series, alcanzando valores de discinesia, con persistencia de la disfunción contráctil tras 60 minutos de reperfusión, y sin diferencias entre ambas series (50% serie Placebo; 41% serie Trimetazidina). Conclusiones: La recuperación de la contractilidad miocárdica tras una isquemia completa en la serie tratada con TMZ no mostró diferencias significativas respecto a la serie Placebo, a diferencia de lo que ocurre con períodos de oclusión más cortos y repetidos.
Objective: The aim of this study is to evaluate the effect of trimetazidine (TMZ) on myocardial systolic dysfunction resulting from an isolated episode of induced coronary ischemia. Methods: In a double-blinded randomized design we studied 13 mongrel anesthetized dogs of either sex (6 of them treated with oral TMZ previously). The anterior descending coronary artery was totally occluded during 15 minutes followed by 60 minutes of reperfusion. Global and regional cardiac variables were recorded in control and ischemic areas. Results: There were no significant differences between TMZ and placebo series with respect to global cardiac function variables. Both series showed no significant variations in global variables during the ischemia-reperfusion process. The shortening fraction in the ischemic area fell significantly during the ischemic period in both TMZ and placebo series reaching dyskinetic values. Myocardial contractility dysfunction persisted after 60 minutes of reperfusion in both series with no significant differences (41% vs 50% placebo). Conclusions: Contrary to shorter and repeated occlusion periods, myocardial contractility recovery after a complete episode of ischemia did not show significant differences between TMZ-treated and placebo series.
Assuntos
Animais , Cães , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miocárdio Atordoado/tratamento farmacológico , Trimetazidina/farmacologia , Vasodilatadores/farmacologia , Circulação Coronária/efeitos dos fármacos , Circulação Coronária/fisiologia , Avaliação Pré-Clínica de Medicamentos , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Modelos Animais , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio Atordoado/fisiopatologia , Miocárdio/metabolismo , Distribuição AleatóriaRESUMO
OBJECTIVE: The aim of this study is to evaluate the effect of trimetazidine (TMZ) on myocardial systolic dysfunction resulting from an isolated episode of induced coronary ischemia. METHODS: In a double-blinded randomized design we studied 13 mongrel anesthetized dogs of either sex (6 of them treated with oral TMZ previously). The anterior descending coronary artery was totally occluded during 15 minutes followed by 60 minutes of reperfusion. Global and regional cardiac variables were recorded in control and ischemic areas. RESULTS: There were no significant differences between TMZ and placebo series with respect to global cardiac function variables. Both series showed no significant variations in global variables during the ischemia-reperfusion process. The shortening fraction in the ischemic area fell significantly during the ischemic period in both TMZ and placebo series reaching dyskinetic values. Myocardial contractility dysfunction persisted after 60 minutes of reperfusion in both series with no significant differences (41% vs 50% placebo). CONCLUSIONS: Contrary to shorter and repeated occlusion periods, myocardial contractility recovery after a complete episode of ischemia did not show significant differences between TMZ-treated and placebo series.
Assuntos
Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miocárdio Atordoado/tratamento farmacológico , Trimetazidina/farmacologia , Vasodilatadores/farmacologia , Animais , Circulação Coronária/efeitos dos fármacos , Circulação Coronária/fisiologia , Cães , Avaliação Pré-Clínica de Medicamentos , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Modelos Animais , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio Atordoado/fisiopatologia , Miocárdio/metabolismo , Distribuição AleatóriaRESUMO
La terapia con solución de glucosa insulina y potasio en el infarto o solución GIK fue inicialmente utilizada por Sodi-Pallares. Desde entonces muchos trabajos con esta solución han sido publicados con resultados disímiles. Sin embargo el resultado de un meta-análisis reciente, que incluye sólo trabajos randomizados con dosis adecuadas de GIK, parece confirmar la disminución de la mortalidad asociada a solución GIK. Para comprender mejor los fundamentos y posibles mecanismos de beneficio con el empleo de la solución GIK en el infarto del miocardio, revisaremos primero el metabolismo miocárdico normal y en condiciones de isquemia, luego el daño por reperfusión post infarto y los efectos de la solución GIK en el miocardio. Por último, analizaremos las experiencias clínicas publicadas con esta terapia