RESUMO
BACKGROUND AND PURPOSE: Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP-binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds. EXPERIMENTAL APPROACH: The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single-cell Ca2+ imaging. A specific effect on RyR2 was confirmed using single channel recordings. Ventricular myocytes were also used to determine if drug-induced changes in SOICR could be reversed using anti-SOICR agents. KEY RESULTS: Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti-SOICR agent VK-II-86. CONCLUSIONS AND IMPLICATIONS: Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti-SOICR activity may represent an improved treatment option for patients.
Assuntos
Imidazóis/farmacologia , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Pirimidinas/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Sunitinibe/farmacologia , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Ligantes , Masculino , Células Musculares/efeitos dos fármacos , Fenazinas , Ratos , Ratos Sprague-Dawley , Análise de Célula Única , Relação Estrutura-AtividadeRESUMO
Solid internal fixation of fractures of the ribs and thorax producing a flail chest is described using a new technic which permits early mobilisation of the patient, immediate spontaneous respiration, abolition of pain, early respiratory physiotherapy, and reduces the danger of respiratory complications due to artificial ventilation, and permenent sequelae due to a secondary deformity of the thoracic cage. Our experience of the method has permitted us to determine its indications and limits.