Decreased BDNF levels in amygdala and hippocampus after intracerebroventricular administration of ouabain / Diminuição dos níveis de BDNF em amígdala e hipocampo após a administração intracerebroventricular de ouabaína

OBJECTIVE: The present study aims to investigate the effects of ouabain intracerebroventricular injection on BDNF levels in the amygdala and hippocampus of Wistar rats.METHODS: Animals received a single intracerebroventricular injection of ouabain (10-3 and 10-2 M) or artificial cerebrospinal fluid and immediately, 1h, 24h, or seven days after injection, BDNF levels were measured in the rat's amygdala and hippocampus by sandwich-ELISA (n = 8 animals per group).RESULTS: When evaluated immediately, 3h, or 24h after injection, ouabain in doses of 10-2 and 10-3 M does not alter BDNF levels in the amygdala and hippocampus. However, when evaluated seven days after injection, ouabain in 10-2 and 10-3 M, showed a significant reduction in BDNF levels in both brain regions evaluated.DISCUSSION: In conclusion, we propose that the ouabain decreased BDNF levels in the hippocampus and amygdala when assessed seven days after administration, supporting the Na/K ATPase hypothesis for bipolar illness.

OBJETIVO: O presente estudo tem como objetivo investigar os efeitos da injeção intracerebroventricular de ouabaína sobre os níveis de BDNF na amígdala e no hipocampo de ratos Wistar.MÉTODOS: Os animais receberam uma única injeção intracerebroventricular de ouabaína (10-3 and 10-2 M) ou fluido cerebroespinhal artificial e, imediatamente, 3h, 24h ou sete dias após a injeção, os níveis de BDNF foram mensurados na amígdala e hipocampo dos ratos por ELISA sandwich (n = 8 animais por grupo).RESULTADOS: Quando avaliados imediatamente após a injeção, 3h ou 24h, ouabaína nas doses 10-2 e 10-3 M não alterou os níveis de BDNF em ambas as estruturas avaliadas. Entretanto, quando avaliados sete dias após a injeção, ouabaína nas doses 10-2 e 10-3 M mostrou uma significante redução nos níveis de BDNF em amígdala e hipocampo.CONCLUSÃO: Em conclusão, propõe-se que a administração de ouabaína diminuiu os níveis de BDNF em amígdala e hipocampo quando avaliados sete dias após a injeção, suportando a hipótese da participação da Na/K ATPase no transtorno bipolar.

Hypertensive effects of the iv administration of picomoles of ouabain

Ouabain, an endogenous digitalis compound, has been detected in nanomolar concentrations in the plasma of several mammals and is associated with the development of hypertension. In addition, plasma ouabain is increased in several hypertension models, and the acute or chronic administration of ouabain increases blood pressure in rodents. These results suggest a possible association between ouabain and the genesis or development and maintenance of arterial hypertension. One explanation for this association is that ouabain binds to the α-subunit of the Na+ pump, inhibiting its activity. Inhibition of this pump increases intracellular Na+, which reduces the activity of the sarcolemmal Na+/Ca2+ exchanger and thereby reduces Ca2+ extrusion. Consequently, intracellular Ca2+ increases and is taken up by the sarcoplasmic reticulum, which, upon activation, releases more calcium and increases the vascular smooth muscle tone. In fact, acute treatment with ouabain enhances the vascular reactivity to vasopressor agents, increases the release of norepinephrine from the perivascular adrenergic nerve endings and promotes increases in the activity of endothelial angiotensin-converting enzyme and the local synthesis of angiotensin II in the tail vascular bed. Additionally, the hypertension induced by ouabain has been associated with central mechanisms that increase sympathetic tone, subsequent to the activation of the cerebral renin-angiotensin system. Thus, the association with peripheral mechanisms and central mechanisms, mainly involving the renin-angiotensin system, may contribute to the acute effects of ouabain-induced elevation of arterial blood pressure.

Effects of small doses of ouabain on the arterial blood pressure of anesthetized hypertensive and normotensive rats

Ouabain increases vascular resistance and may induce hypertension by inhibiting the Na+ pump. The effects of 0.18 and 18 æg/kg, and 1.8 mg/kg ouabain pretreatment on the phenylephrine (PHE; 0.1, 0.25 and 0.5 æg, in bolus)-evoked pressor responses were investigated using anesthetized normotensive (control and uninephrectomized) and hypertensive (1K1C and DOCA-salt treated) rats. Treatment with 18 æg/kg ouabain increased systolic and diastolic blood pressure in all groups studied. However, the magnitude of this increase was larger for the hypertensive 1K1C and DOCA-salt rats than for normotensive animals, while the pressor effect of 0.18 æg/kg ouabain was greater only in DOCA-salt rats. A very large dose (1.8 mg/kg) produced toxic effects on the normotensive control but not on uninephrectomized or 1K1C rats. Rat tail vascular beds were perfused to analyze the effects of 10 nM ouabain on the pressor response to PHE. In all animals, 10 nM ouabain increased the PHE pressor response, but this increase was larger in hypertensive DOCA-salt rats than in normotensive and 1K1C rats. Results suggested that a) increases in diastolic blood pressure induced by 18 æg/kg ouabain were larger in hypertensive than normotensive rats; b) in DOCA-salt rats, smaller ouabain doses had a stronger effect than in other groups; c) hypertensive and uninephrectomized rats were less sensitive to toxic doses of ouabain, and d) after treatment with 10 nM ouabain isolated tail vascular beds from DOCA-salt rats were more sensitive to the pressor effect of PHE than those from normotensive and 1K1C hypertensive rats. These data suggest that very small doses of ouabain, which might produce nanomolar plasma concentrations, enhance pressor reactivity in DOCA-salt hypertensive rats, supporting the idea that endogenous ouabain may contribute to the increase and maintenance of vascular tone in hypertension

Papel de la adenosina sobre la acción antiarrítmica de los digitálicos / Role of adenosine on the antiarrhythmic action of digitalis

La acción de la adenosina sobre el periodo refractario funcional de los tejidos auriculares y en la cancelación del flutter auricular, es semejante a la de los digitálicos. Tal hecho sugiere la posible existencia de una participación adenílica en la acción digitálica. Por ello medimos las concentraciones plasmáticas de adenosina al infundir ouabaína, e investigamos el efecto del digitálico sobre el periodo refractario de tejidos auriculares y sobre el flutter en condiciones de inhibición colinérgico y bloqueo purinérgico. En perros, se administró ouabaína hasta inducir fibrilación ventricular. Se obtuvo sangre del seno coronario y de la vena femoral, midiendo la adenosina por cromatagrafía de líquidos. El periodo refractario se midió con la ténica del estímulo extra acoplado. El flutter se indujo al estimular el haz internodal posterior. Los resultados muestran que la concentración de adenosina se elevó más de 100 por ciento en plama de seno coronario; el efecto de la ouabaína sobre el periodo refractario no se modificó con la inhibición colinérgica, pero sí fue inhibido por aminofilina; el digitálico modificó su acción en la cancelación del flutter en presencia de aminofilina. Conclusión: en la acción antiarrítmica de los digitálicos parece participar un componente adenílico que resulta de la liberación de adenosina del corazón

Efectos de los compuestos digitálicos sobre la relajación inducida por K+ en anillos de aorta / Effects of digtalis compounds on potassium induced relaxation of aortic rings

Cambios en la estructura de los digitálicos afectan su potencia y modifican sus propiedades farmacológicas sobre el músculo cardiaco. La relajación del músculo liso vascular inducida por KCl ha sido utilizada como índice de la actividad de la ATPasa de Na+K+ arterial, ya que la inhibición experimental de la actividad de esta enzima (incubación con ouabían, eliminación de Na+ y K+ extracelular), reduce la relajación inducida por KCl en anillo arteriales. En el presente estudio, examinamos si los cambios en la estructura química de la ouabaína, modifican su capacidad para inhibir la ATPasa de Na+K+ arterial. Comparamos los efectos de la ouabaína, con los de la ouabagenina, en los cambios del tono vascular de anillo de aorta de rata. Los cambios en el tono basal vascular, fueron potenciados por la ouabaína y no fueron afectados por la ouabagenina. La contracción máxima producida por fenilefrina fue inhibida por la ouabaína y no por la ouabagenina. La relajación producida por KCl fue bloqueada por ouabaína, mientras que la contracción inducida por KCl fue únicamente inhibida por ouabaína. Los presentes resultados nos permiten sugerir que la eliminación de la molécula de 1-Ramnosa en la estructura de la ouabaína disminuye su capacidad de inhibir la ATPasa de Na+ K+ arterial.

Tratamiento prolongado de la insuficiencia cardíaca crónica con ouabaína

Se describe el tratamiento con ouabaína (o estrofantina) en 90 casos de insuficiencia cardíaca cróica congestiva avanzada, considerada irreductible, todos en grado IV de la clasificación de N Y H A, durante un tiempo que varióo entre 8 días y 5 años 10 meses. La inyección se hizo en ocasiones diaria, o día por medio, o dos días por medio, hasta una por semana. La dosis máxima diaria empleada fue de 0.25 mg. Dosis más altas deben ser consideradas peligrosas. Se hizo un estudio sobre la aplicación de estrofantina en pacientes digitalizados y se observó que no es necesario esperar dos semanas y que se puede emplear aún al día siguiente, con precauciones, y mejor dejando dos o más días de intervalo entre una droga y otra