Mechanism of the negative inotropic effect of naringin in mouse heart

Resumen Context: Naringin (NRG) is the major flavonoid (flavanone glycoside) in grapefruit juice. Its biological activity has been only partially characterized and little is known about the mechanism of the negative inotropic action of this flavonoid. Aims: To evaluate the effects of NRG on the surface electrogram (ECG) and the force of contraction (FC) of mice hearts as well as on the sodium (INa), calcium (ICaL) and Na + Ca exchange (INaCaX) currents of enzymatically isolated mouse ventricular cardiomyocytes. Methods: ECG and FC were recorded on mouse hearts perfused in a Langendorff column. Ventricular cardiomyocytes were enzimatically dissociated and ionic currents recorded with the patch-clamp technique. Results: NRG increased RR interval and shortened corrected QT only at high concentrations (30-100 μM). However, at a fixed heart rate, it decreased FC with an IC50 of 0.4 μM. NRG reduced INa with an IC50 of 0.07 μM but with a maximal inhibition of 60 %. NRG also depressed ICaL with an IC50 of 0.013 μM and increased its fast inactivation time constant. The effects on ICaL were not voltage-dependent. INaCaX was not affected by NRG. Conclusions: Our results indicate that NRG exerts a negative inotropic effect in mice hearts that could be explained by a decrease in INa and ICaL. These actions should be taken into account when considering this molecule either as a dietetic supplement or as a template to develop therapeutic agents for human diseases. Contexto: La naringina (NRG) es el principal flavonoide (glicosido de flavanona) en el jugo de toronja. Su actividad biologica ha sido solo parcialmente caracterizada y poco se conoce acerca del mecanismo de la accion inotropica negativa de este flavonoide. Objetivos: Evaluar los efectos de la NRG sobre el electrograma de superficie (ECG) y la fuerza de contraccion (FC) de corazones de raton, asi como sobre las corrientes de sodio (INa), calcio (ICaL) y del intercambiador Na Ca (INaCaX) en cardiomiocitos ventriculares de raton, aislados enzimaticamente. Metodos: El ECG y la FC se registraron en corazones de raton perfundidos en una columna de Langendorff. Los cardiomiocitos ventriculares se disociaron enzimaticamente y las corrientes ionicas se registraron con la tecnica de patch-clamp. Resultados: La NRG incremento el intervalo RR intervalo y acorto el QT solo a altas concentraciones (30-100 μM). No obstante, a frecuencia cardiaca fija, disminuyo la FC con un IC50 de 0.4 μM. La NRG redujo INa con un IC50 de 0.07 μM pero con una maxima inhibicion de 60 %. La NRG tambien redujo ICaL con un IC50 de 0.013 μM e incremento su constante de inactivacion rapida. Los efectos sobre ICaL no fueron dependientes del potencial. La INaCaX no fue afectada por la NRG. Conclusiones: Nuestros resultados indican que la NRG ejerce un efecto inotropico negativo en corazones de raton que puede ser explicado por una reduccion en INa e ICaL. Esas acciones deben ser tomadas en cuenta al considerar a esta molecula como suplemento dietetico o como plantilla para desarrollar nuevos agentes terapeuticos para tratar las enfermedades