Hypothalamic digoxin and regulation of body mass index.

The hypothalamus produces digoxin, an endogenous membrane Na+-K+ ATPase inhibitor and regulator of neurotransmission. Digoxin being a steroidal glycoside, is synthesised by the isoprenoid pathway. In view of the reports of elevated digoxin levels in metabolic syndrome X with high body mass index, the isoprenoid pathway mediated biochemical cascade was assessed in individuals with high and low body mass index. It was also assessed in individuals with differing hemispheric dominance to find out the relationship between digoxin status, body mass index and hemispheric dominance. The isoprenoid pathway metabolites, tryptophan / tyrosine catabolic patterns and membrane composition were assessed. In individuals with high body mass index an upregulated isoprenoid pathway with increased HMG CoA reductase activity, serum digoxin and dolichol levels and low ubiquinone levels were observed. The RBC membrane Na+-K+ ATPase activity and serum magnesium levels were decreased. The tyrosine catabolites (dopamine, morphine, epinephrine and norepinephrine) were reduced and the tryptophan catabolites (serotonin, quinolinic acid, strychnine and nicotine) were increased. There was an increase in membrane cholesterol : phospholipid ratio and a reduction in membrane glycoconjugates in individuals with high body mass index. The reverse patterns were seen in individuals with low body mass index. The patterns in individuals with high body mass index and low body mass index correlated with right hemispheric dominance and left hemispheric dominance respectively. Hemispheric dominance and digoxin status regulates the differential metabolic pattern observed in individuals with high and low body mass index.

The isoprenoid pathway in lone atrial fibrillation with embolic stroke.

BACKGROUND: The isoprenoid pathway was assessed and compared in patients of lone atrial fibrillation with embolic stroke as well as in patients with right hemispheric, left hemispheric and bihemispheric dominance to determine the role of hemispheric dominance in its pathogenesis. METHODS AND RESULTS: The activities of hydroxyl methyl glutaryl-CoA reductase and RBC sodium-potasium ATPase as well as serum levels of plasma magnesium, digoxin, dolichol and ubiquinone were measured. The tyrosine/tryptophan catabolic patterns, glycoconjugate metabolism, free radical metabolism and RBC membrane composition were also assessed. In patients with lone atrial fibrillation with embolic stroke, there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites: and an increase in the cholesterol: phospholipid ratio with a reduction in the glycoconjugate levels of the RBC membrane. The same biochemical patterns were obtained in individuals with right hemispheric dominance whereas the patterns were reversed in patients with left hemispheric dominance. CONCLUSIONS: Lone atrial fibrillation with embolic stroke is associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This occurs in right hemisphere-dominant individuals.

Digoxin and membrane sodium potassium ATPase inhibition in cardiovascular disease.

Kerala has a high incidence of mucoid angiopathy, metabolic syndrome X and endomyocardial fibrosis. Magnesium deficiency has been reported in these disorders even though the Keralite diet has adequate magnesium. A possible cause of magnesium deficiency is the increased digoxin, a potent inhibitor membrane Na(+)-K+ ATPase which can lead to magnesium depletion. Digoxin is known to be synthesised by the hypothalamus and other tissues and can also be obtained from plant sources in the diet. Inhibition of Na(+)-K+ ATPase can cause intracellular magnesium depletion and increase in intracellular calcium. In view of these, a study has been carried out on the activity of membrane Na(+)-K+ ATPase, using RBC membrane, serum digoxin, magnesium and glycosaminoglycan levels in patients of mucoid angiopathy, endomyocardial fibrosis and syndrome X. Significant decrease in the membrane Na(+)-K+ ATPase was observed in patients while serum digoxin levels showed an increase. Serum magnesium was significantly lower while glycosaminoglycan levels were increased. The inhibition of Na(+)-K+ ATPase activity may be due to increase in endogenous and/or exogenous digoxin. This inhibition leads to depletion of intracellular magnesium and an increase in intracellular calcium load. The role of underlying magnesium-related insulin resistance and the consequence of this intracellular magnesium and calcium alteration in the pathogenesis of these disorders is discussed.

Isoprenoid pathway and free radical generation and damage in neuropsychiatric disorders.

Two substances which are products of the isoprenoid pathway, can participate in lipid peroxidation. One is digoxin, which by inhibiting membrane Na(+)-K+ ATPase, causes increase in intracellular Ca2+ and depletion of intracellular Mg2+, both effects contributing to increase in lipid peroxidation. Ubiquinone, another products of the pathway is a powerful membrane antioxidant and its deficiency can also result in defective electron transport and generation of reactive oxygen species. In view of this and also in the light of some preliminary reports on alteration in lipid peroxidation in neuropsychiatric disorders, a study was undertaken on the following aspects in some of these disorders (primary generalised epilepsy, schizophrenia, multiple sclerosis, Parkinson's disease and CNS glioma)--1) concentration of digoxin, ubiquinone, activity of HMG CoA reductase and RBC membrane Na(+)-K+ ATPase 2) activity of enzymes involved in free radical scavenging 3) parameters of lipid peroxidation and 4) antioxidant status. The result obtained indicates an increase in the concentration of digoxin and activity of HMG CoA reductase, decrease in ubiquinone levels and in the activity of membrane Na(+)-K+ ATPase. There is increased lipid peroxidation as evidenced from the increase in the concentration of MDA, conjugated dienes, hydroperoxides and NO with decreased antioxidant protection as indicated by decrease in ubiquinone, vit E and reduced glutathione in schizophrenia, Parkinson's disease and CNS glioma. The activity of enzymes involved in free radical scavenging like SOD, catalase, glutathione peroxidase and glutathione reductase is decreased in the above diseases. However, there is no evidence of any increase in lipid peroxidation in epilepsy or MS. The role of increased operation of the isoprenoid pathway as evidenced by alteration in the concentration of digoxin and ubiquinone in the generation of free radicals and protection against them in these disorders is discussed.

Depuración de digoxina mediante diálisis gastrointestinal con carbón activado / Digoxin depuration by means of gastrointestinal dialysis with activated charcoal in five intoxicated children

La intoxicación por digoxina suele resultar del estrecho margen que hay entre las concentraciones plasmáticas terapéuticas y tóxicas del fármaco: 1.02.5 vs>2.5 nmol/L(0.8-2.0vs.>2.0 ng/mL). El tratmaiento de la intoxicación consiste en medidas generales de sostén y sintomáticas, y en medidas para depurar el fármaco. Dado que su volumen de distribución es muy alto (Vd=7 L/kg), los procedimientos dialíticos convencionales no son útiles y el empleo de fragmentos de anticuerpos específicos de digoxina (Fab), aunque útil, es costoso y no deisponible en nuestro país. Como alternativa está la diálisis gastrointestinal con dosis repetidad de carbón activado. El procedimiento se empleó con buenos resultados en cinco niños intoxicados; además de la mejoría clínica, se obtuvo una rápidad depuración de la digoxina. el promedio de las concentraciones plasmáticas iniciales fue de 6.75 nmol/L(5.4 ng/mL) y a las 24 horas de 2.1 nmol/L(1.7 ng/mL), con un descenso neto de 68.6 por ciento (p<0.05). La vida media de eliminación promediada fue de 20.6 horas (referencia 69ñ25 horas en menores de tres meses y 45ñ7.8 horas en mayores de cuatro meses). No hubo efectos adversos atribuibles al procedimiento

Caracterización de un factor endógeno con actividad digitálica en el corazón de cobayo II: unión al receptor / Characterization of an endogenous digitalis-like factor in mammals

En este trabajo se continuaron los estudios sobre la presencia de un factor digitálico endógeno en mamíferos. Un extracto acuoso de corazón de cobayo fue parcialmente purificado por cromatografia de líquidos. El extracto desplazó la unión específica de (H) ouabaina a la Na,K-ATP asa de corazón de cobayo obteniéndose una curva de desplazamiento paralela a la observada cuando se uso digoxina como agente desplazante. Los datos sugieren que la actividad del extracto es debida a la presencia de un factor que reconoce al sitio de unión de los digitálicos y no a iones o a lípidos. Además, el extracto mostró reactividad cruzada con anticuerpos antidigoxina y con anticuerpos antidigitoxina de manera similar a los antígenos específicos. Los resultados apoyan la hipótesis de la existencia, en mamíferos, de un ligando endógeno del receptor digitálico que podría ser un egulador fisiológico de la bomba de sodio