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Redalyc.Mechanism of the Negative Inotropic Effect of Naringin in Mouse Journal of Pharmacy & Pharmacognosy Research E-ISSN: 0719-4250 [email protected] Asociación de Académicos de Ciencias Farmacéuticas de Antofagasta Chile Alvarez -Collazo, Julio; López -Medina, Ana I.; Rodríguez, Armando A.; Alvarez, Julio L. Mechanism of the negative inotropic effect of naringin in mouse heart Journal of Pharmacy & Pharmacognosy Research, vol. 2, núm. 5, septiembre-octubre, 2014, pp. 148-157 Asociación de Académicos de Ciencias Farmacéuticas de Antofagasta Antofagasta, Chile Available in: http://www.redalyc.org/articulo.oa?id=496050270005 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative © 2014 Journal of Pharmacy & Pharmacognosy Research, 2 (5), 148-157 ISSN 0719-4250 http://jppres.com/jppres Original Article | Artículo Original Mechanism of the negative inotropic effect of naringin in mouse heart [Mecanismo del efecto inotrópico negativo de la naringina en el corazón de ratón] Julio Alvarez-Collazoa, Ana I. López-Medinaa, Armando A. Rodríguezb, Julio L. Alvareza* aLaboratorio de Electrofisiología. Instituto de Cardiología y Cirugía Cardiovascular. 17 N° 702, Vedado, La Habana, Cuba. bResearch Group for Experimental and Clinical Peptide Chemistry. Hannover Medical School, Hannover, Germany. * E-mail: [email protected] Abstract Resumen Context: Naringin (NRG) is the major flavonoid (flavanone glycoside) in Contexto: La naringina (NRG) es el principal flavonoide (glicósido de grapefruit juice. Its biological activity has been only partially flavanona) en el jugo de toronja. Su actividad biológica ha sido solo characterized and little is known about the mechanism of the negative parcialmente caracterizada y poco se conoce acerca del mecanismo de la inotropic action of this flavonoid. acción inotrópica negativa de este flavonoide. Aims: To evaluate the effects of NRG on the surface electrogram (ECG) Objetivos: Evaluar los efectos de la NRG sobre el electrograma de and the force of contraction (FC) of mice hearts as well as on the sodium superficie (ECG) y la fuerza de contracción (FC) de corazones de ratón, así + 2+ (INa), calcium (ICaL) and Na - Ca exchange (INaCaX) currents of como sobre las corrientes de sodio (INa), calcio (ICaL) y del intercambiador + 2+ enzymatically isolated mouse ventricular cardiomyocytes. Na - Ca (INaCaX) en cardiomiocitos ventriculares de ratón, aislados Methods: ECG and FC were recorded on mouse hearts perfused in a enzimáticamente. Langendorff column. Ventricular cardiomyocytes were enzimatically Métodos: El ECG y la FC se registraron en corazones de ratón dissociated and ionic currents recorded with the patch-clamp technique. perfundidos en una columna de Langendorff. Los cardiomiocitos Results: NRG increased RR interval and shortened corrected QT only at ventriculares se disociaron enzimáticamente y las corrientes iónicas se high concentrations (30-100 µM). However, at a fixed heart rate, it registraron con la técnica de patch-clamp. decreased FC with an IC50 of 0.4 µM. NRG reduced INa with an IC50 of 0.07 Resultados: La NRG incrementó el intervalo RR intervalo y acortó el QT µM but with a maximal inhibition of 60 %. NRG also depressed ICaL with solo a altas concentraciones (30-100 µM). No obstante, a frecuencia an IC50 of 0.013 µM and increased its fast inactivation time constant. The cardíaca fija, disminuyó la FC con un IC50 de 0.4 µM. La NRG redujo INa effects on ICaL were not voltage-dependent. INaCaX was not affected by con un IC50 de 0.07 µM pero con una máxima inhibición de 60 %. La NRG NRG. también redujo ICaL con un IC50 de 0.013 µM e incrementó su constante de Conclusions: Our results indicate that NRG exerts a negative inotropic inactivación rápida. Los efectos sobre ICaL no fueron dependientes del potencial. La INaCaX no fue afectada por la NRG. 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 Conclusiones: Nuestros resultados indican que la NRG ejerce un efecto molecule either as a dietetic supplement or as a template to develop inotrópico negativo en corazones de ratón que puede ser explicado por therapeutic agents for human diseases. una reducción en INa e ICaL. Esas acciones deben ser tomadas en cuenta al considerar a esta molécula como suplemento dietético o como plantilla para desarrollar nuevos agentes terapéuticos para tratar las enfermedades en humanos. Keywords: Calcium; cardiac; flavonoids; naringenin, naringin; sodium. Palabras Clave: Calcio; cardíaco; flavonoides; naringenina; naringina; sodio. ARTICLE INFO Received | Recibido: October 16, 2014. Received in revised form | Recibido en forma corregida: October 28, 2014. Accepted | Aceptado: October 29, 2014. Available Online | Publicado en Línea: October 30, 2014. Declaration of interests | Declaración de Intereses: The authors declare no conflict of interest. Funding | Financiación: This study was supported by Ministry of Public Health of Cuba (Research Project N° 1301002). _____________________________________ Alvarez-Collazo et al. Negative inotropic effect of naringin INTRODUCTION there is still the need of investigations about the possible direct cardiovascular physiological ac- There is evidence for an association between tions of naringin. Saponara et al. (2006) showed high dietary intake of flavonoids and a reduction that naringin could increase the conductance of of myocardial infarction and stroke (Hertog et al., vascular smooth muscle calcium-activated pota- 2012; Keli et al., 1996). It is widely accepted that these ssium ion channels (BK(Ca)) but exhibited a poor natural compounds could have a potential thera- vasorelaxing action in rat aortic rings compared peutic value in the prevention and treatment of to its aglycone naringenin. Recently, Saponara et cardiovascular diseases (Benavente-García and Castillo, al. (2011) described that a number of flavonoids 2008; Habauzit and Morand, 2012) due to their anti- stimulated or inhibited ICaL in rat tail artery oxidant, anti-inflammatory, anti-proliferative and myocytes. They found that naringin and anti-thrombotic actions (see for reviews Bharti et al., naringenin modestly inhibited ICaL. We have 2014; Wright et al., 2013). However, the intracellular previously reported that naringin, at pharmacolo- modulator actions of flavonoids are diverse and gical relevant concentrations, induced contrac- complex (Wright et al., 2013) and can be affected by tion of rat aortic rings and exerted a modest sex, lifestyle, disease states and interactions with negative inotropic effect on isolated rat hearts drugs thus limiting their impact on human health (López-Medina et al., 2014). Since naringin could be (Wright et al., 2013; Chanet et al., 2012). Nonetheless, used as a dietary supplement, antioxidant, these compounds are extremely interesting as antiinflammatory and even as a template to molecular templates to design drugs with better develop cardiovascular drugs, it is important to pharmacological profiles for the treatment of investigate its actions on the voltage-dependent + 2+ human cardiovascular diseases. Na and Ca channels and on the current + 2+ The flavanone naringin is the major flavonoid generated by the Na - Ca exchanger in an in grapefruit juice, an important dietary source of attempt to elucidate the mechanism of the flavonoids, and gives the grapefruit juice its bitter negative inotropic action of this flavonoid. taste (Peterson et al., 2006). When it is ingested, NRG is transformed and converted to several meta- MATERIALS AND METHODS bolites (including naringenin) in blood and urine. However, naringin (and naringenin) could be Chemicals detected in plasma around 5 hours after oral Naringin (4’,5,7-trihydroxyflavanone 7-rham- administration (Bharti et al., 2014; Fuhr and Kummert, noglucoside; C27H32O14, PubChem CID: 25075; 1995). Naringin seems to have a cardioprotective >95% HPLC), nifedipine (1,4-dihydro-2,6-dime- action in isoproterenol-induced myocardial thyl-4-(2-nitrophenyl)-3,5-pyridinedicarbo-xylic infarction in rats (Rajadurai and Prince, 2007). In acid dimethyl ester; C17H18N2O6; PubChem CID: stroke-prone spontaneously hypertensive rats, 4485; >98% HPLC) and lidocaine (2-diethylami- orally-administered naringin was reported to no-N-(2,6-dimethylphenyl)acetamide; C14H22N2O; suppress the age-related increase in blood PubChem CID: 3676; 99.9% HPLC) were purcha- pressure, to significantly decrease thrombotic sed from Sigma Aldrich and were prepared in tendency and to increase nitric oxide (NO) pro- ethanol as 0.1 M (naringin and lidocaine) and 10 duction thus improving endothelium-dependent µM (nifedipine) stock solutions. All other vasodilation (Ikemura et al., 2012). Nevertheless, part chemicals were also from Sigma Aldrich. of these effects could be also probably due to the actions of naringenin, the aglycone formed du- Animals ring the cleavage of the sugar moiety of naringin after its ingestion (Fuhr and Kummert, 1995). Naringe- Experiments were performed using male adult nin, by activating mitochondrial BK potassium C57BL/6 (7-8 weeks) mice according to the channels could protect against ischemia- procedures approved by the Centro Nacional para reperfusion injury (Testai et al., 2013). However, la Producción de Animales de Laboratorio http://jppres.com/jppres J Pharm Pharmacogn Res (2014) 2(5): 149 Alvarez-Collazo
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