Asunto(s)
Gripe Humana , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Humanos , Virus de la Influenza B , Gripe Humana/diagnóstico , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Virus Sincitial Respiratorio Humano/genética , Sensibilidad y EspecificidadRESUMEN
Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially life-threatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into two groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: (i) single IV injection of saline, (ii) lipid emulsion (Intralipid(®) ), (iii) levobupivacaine, (iv) combination levobupivacaine-Intralipid(®) . Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax ). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation, and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins, and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/dtmax . At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid(®) quickly improved haemodynamics. However, beneficial effects of Intralipid(®) were less clear after myocardial ischemia.
Asunto(s)
Anestésicos Locales/toxicidad , Bupivacaína/análogos & derivados , Sistema de Conducción Cardíaco/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Mitocondrias Cardíacas/efectos de los fármacos , Isquemia Miocárdica/complicaciones , Miocitos Cardíacos/efectos de los fármacos , Fosfolípidos/farmacología , Aceite de Soja/farmacología , Potenciales de Acción , Anestésicos Locales/administración & dosificación , Animales , Presión Arterial/efectos de los fármacos , Bradicardia/inducido químicamente , Bradicardia/fisiopatología , Bradicardia/prevención & control , Bupivacaína/administración & dosificación , Bupivacaína/toxicidad , Calcio/metabolismo , Citoprotección , Modelos Animales de Enfermedad , Emulsiones/farmacología , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intravenosas , Levobupivacaína , Peroxidación de Lípido/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fosforilación Oxidativa/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Sus scrofa , Factores de Tiempo , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/prevención & control , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
The aim of this study was to determine whether amlodipine and/or perindoprilate injected intravenously (iv) prior to ischemia exerted protective effects on mitochondria structural and functional alterations induced by ischemia and aggravated by reperfusion. Heart rate, the duration of monophasic action potentials (dMAP), peak of the time derivative of left ventricular pressure (LV dP/dt max), mitochondria structural and functional parameters in the left ventricle ischemic area were measured after 45-min ischemia and 1-min reperfusion in domestic pigs either untreated or pretreated with amlodipine, perindoprilate or amlodipine + perindoprilate. Ischemia-reperfusion (I/R) induced tachycardia, reduced dMAP and LV dP/dt max, and causes alterations of mitochondria structural and functional parameters with decreased oxygen consumption, increased reactive oxygen species production and reduced calcium retention capacity (CRC) with opening of mitochondrial permeability transition pores. This opening is mainly due to oxidative stress and calcium overload and seems to be the pivotal event in cell death after I/R. No drug treatment changed haemodynamic and electrophysiological parameters, but amlodipine and perindoprilate, either alone or combined, prevented mitochondrial alterations but only partially. The preservation of mitochondrial structure and functions reported in our study probably plays an important role in preventing calcium overload and mPTP opening during myocardial I/R by a specially increased CRC, which can explain their cardioprotective effects.
Asunto(s)
Amlodipino/farmacología , Ventrículos Cardíacos/efectos de los fármacos , Indoles/farmacología , Mitocondrias/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Calcio/metabolismo , Muerte Celular/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Isquemia Miocárdica/metabolismo , Reperfusión Miocárdica/métodos , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , PorcinosRESUMEN
Preventing the consequences of ischemia/reperfusion (I/R)-induced lesions in the clinic requires the administration of pharmacological agents prior to restoring coronary vascularization. The aim of this study was to evaluate the effects of ranolazine and propranolol when administered either alone or combined prior to I/R induction in a pig model. Thirty domestic pigs were randomly assigned to five groups of six animals including (i) sham animals; (ii) untreated animals with 45-min ischemia and 1-min reperfusion; animals administered intravenously with (iii) ranolazine, or (iv) propranolol, or (v) both combined, prior to 45-min ischemia and 1-min reperfusion. The heart rate (HR), duration of monophasic action potentials (dMAP), and peak of the time derivative of left ventricular pressure (LV dP/dt max) were measured during ischemia and after 1 min of reperfusion. Structural and functional parameters of mitochondria were analyzed in tissue samples taken from the left ventricle ischemic area at the end of the experiment. I/R induced expected effects, namely accelerated HR, decreased dMAP and LV dP/dt max, and altered mitochondrial structural and functional parameters including decreased oxygen consumption, increased reactive oxygen species (ROS) production, and reduced calcium retention capacity resulting in the opening of mitochondrial permeability transition pores (mPTP). Ranolazine and propranolol administered either alone or combined prior to I/R significantly decreased all of these deleterious consequences. The protective effects of ranolazine and propranolol are seemingly due to the prevention of calcium overload and resulting lesions in mitochondria.
Asunto(s)
Acetanilidas/uso terapéutico , Cardiotónicos/uso terapéutico , Mitocondrias/efectos de los fármacos , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Piperazinas/uso terapéutico , Propranolol/uso terapéutico , Acetanilidas/administración & dosificación , Acetanilidas/farmacología , Animales , Calcio/metabolismo , Cardiotónicos/administración & dosificación , Cardiotónicos/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Frecuencia Cardíaca/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Consumo de Oxígeno/efectos de los fármacos , Piperazinas/administración & dosificación , Piperazinas/farmacología , Propranolol/administración & dosificación , Propranolol/farmacología , Ranolazina , Especies Reactivas de Oxígeno/metabolismo , Sus scrofaRESUMEN
The involvement of psychotropic drugs in sudden deaths has been highlighted. The objective of this work was to establish a link between selenium levels in heart tissue, psychotropic treatment and sudden death. Selenium levels were measured by electrothermal atomic absorption spectroscopy post-mortem in heart, brain and liver. Histological examination evidenced dilated cardiomyopathy in 45% of cases, left ventricular hypertrophy in 36%, and ischemic coronaropathy in 18%. A significant reduction of myocardial selenium levels compared to controls was seen in patients treated with neuroleptic drugs or meprobamate. No changes in brain or liver selenium levels were seen. These results suggest that selenium deficiency can facilitate sudden death in patients on psychotropic drugs. The reduced activity of glutathione peroxidase due to selenium deficiency can result in augmented oxidative stress in myocardial cells and myocardiopathy leading to sudden death.