RESUMO
Thyroid hormone action has profound consequences for the heart, ranging from atrial fibrillation to hemodynamic collapse. It has long been known that the cardiovascular signs and symptoms seen in thyrotoxicosis resemble those seen in states of catecholamine excess. However, measured concentrations of serum catecholamines in patients with thyrotoxicosis are typically normal or even low, suggesting an increase in the adrenergic responsiveness of the thyrotoxic heart. In spite of several decades of work, the question of whether thyroid hormone increases cardiac adrenergic responsiveness is still controversial. In this brief review, we consider the reasons underlying this controversy, focusing on the complexity of the adrenergic signaling cascade.
Assuntos
Coração/fisiologia , Receptores Adrenérgicos/fisiologia , Hormônios Tireóideos/fisiologia , Cardiopatias/etiologia , Humanos , Tireotoxicose/complicaçõesRESUMO
Whereas many cardiac symptoms of thyrotoxicosis resemble those of the hyperadrenergic state, circulating catecholamines are reduced or normal in this condition. To test the hypothesis that the thyrotoxic heart is hypersensitive to catechol-amines, we studied beta-adrenergic signaling in a transgenic (TG) mouse in which the human type 2 iodothyronine deiodinase (D2) gene is expressed in myocardium. Because D2 converts T4 to T3, the active form of thyroid hormone, the D2 TG mouse exhibits mild, chronic thyrotoxicosis that is limited to the myocardium. In the current study, we determined that cAMP accumulation in response to either norepinephrine or forskolin treatment was increased in isolated ventricular myocardiocytes and membrane-enriched fractions prepared from these D2 TG hearts as compared with wild type. This increase in adenylyl cyclase (AC) Vmax could not be explained by changes in AC isoform expression or changes in the long or short forms of stimulatory G-protein Gsalpha, which were approximately 10% decreased in D2 TG membranes. However, Western analysis and ADP-ribosylation studies suggest that the increase in AC Vmax is mediated by a decrease in the expression of inhibitory G proteins (Gialpha-3 and/or Goalpha). These data suggest that cardiac thyrotoxicosis leads to increased beta-adrenergic responsiveness of cardiomyocytes via alterations in the regulatory G-protein elements of the AC membrane complex.
Assuntos
Iodeto Peroxidase/genética , Miocárdio/metabolismo , Receptores Adrenérgicos beta/metabolismo , Tireotoxicose/metabolismo , Adenilil Ciclases/metabolismo , Animais , Membrana Celular/metabolismo , Células Cultivadas , Colforsina/farmacologia , AMP Cíclico/metabolismo , Feminino , Proteínas de Ligação ao GTP/efeitos dos fármacos , Proteínas de Ligação ao GTP/metabolismo , Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Iodeto Peroxidase/metabolismo , Isoenzimas/metabolismo , Cinética , Masculino , Camundongos , Camundongos Transgênicos , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Norepinefrina/farmacologia , Tireotoxicose/fisiopatologia , Iodotironina Desiodinase Tipo IIRESUMO
A ação do hormônio tireoideano tem consequências profundas no sistema cardiovascular, as quais variam desde fibrilação atrial ao colapso hemodinâmico. Há muito sabe-se que os sinais e sintomas cardiovasculares detectados na tireotoxicose assemelham-se aos observados em estados hiper-adrenérgicos. Entretanto, as concentrações séricas de catecolaminas em pacientes com tireotoxicose são tipicamente normais ou mesmo baixas, sugerindo um aumento na responsividade adrenérgica no coração tireotóxico. A despeito de várias décadas de trabalho, a questão sobre se o hormônio tireoideano aumenta a responsividade adrenérgica é ainda controversa. Nesta revisão, nós consideramos os motivos que alimentam esta controvérsia, focalizando na complexidade da cascata de sinalização adrenérgica.
