Numerical Simulation of the Effect of Sodium Profile on Cardiovascular Response to Hemodialysis

PURPOSE: We developed a numerical model that predicts cardiovascular system response to hemodialysis, focusing on the effect of sodium profile during treatment. MATERIALS and METHODS: The model consists of a 2-compartment solute kinetics model, 3-compartment body fluid model, and 12-lumped-parameter representation of the cardiovascular circulation model connected to set-point models of the arterial baroreflexes. The solute kinetics model includes the dynamics of solutes in the intracellular and extracellular pools and a fluid balance model for the intracellular, interstitial, and plasma volumes. Perturbation due to hemodialysis treatment induces a pressure change in the blood vessels and the arterial baroreceptors then trigger control mechanisms (autoregulation system). These in turn alter heart rate, systemic arterial resistance, and cardiac contractility. The model parameters are based largely on the reported values. RESULTS: We present the results obtained by numerical simulations of cardiovascular response during hemodialysis with 3 different dialysate sodium concentration profiles. In each case, dialysate sodium concentration profile was first calculated using an inverse algorithm according to plasma sodium concentration profiles, and then the percentage changes in each compartment pressure, heart rate, and systolic ventricular compliance and systemic arterial resistance during hemodialysis were determined. A plasma concentration with an upward convex curve profile produced a cardiovascular response more stable than linear or downward convex curves. CONCLUSION: By conducting numerical tests of dialysis/cardivascular models for various treatment profiles and creating a database from the results, it should be possible to estimate an optimal sodium profile for each patient.

Alteraciones enzimáticas séricas en ratas tratadas con bisulfito de sodio / Changes in serum enzymes in rats treated with sodium bisulfite

Inorganic sulphites are chemical compounds with antioxidative, antibacterial and antimycotic properties diffusely employed in agro-food and pharmaceutical industries. In spite of their continuous use there still are many questions regarding their safety, and their possible influence in several nutrients and enzymatic systems, as according to reports in the literature cited. In this study it is determined the effect of increasing doses of sodium bisulphite, 10 to 50 mg/kg/day, injected intramuscularly during seven days on the activity of the following serum enzymes: phosphohexoseisomerase (PHI), gamma-glutamyltranspeptidase (gamma-GT), cholinesterase (CHE), arginase, acid maltase (AM), alkaline phosphatase (AIP), lactic dehydrogenase (LDH), transaminases (GOT and GPT) and 5'-nucleotidase (5'-N) on male Wistar rats (treated groups). The results indicate that in rats treated with sodium bisulphite there is a significant increase (p < 0.05) in the activity of PHI, gamma-GT, arginase, AIP, GOT, GPT and 5'-N as well as an equally significant decrease (p < 0.05) in the activity of LDH, AM and CHE; these variations are proportional to the doses of the compound applied. These findings indicate there is cellular damage to rat liver, kidney orothers organs as a result of bisulphite injected or by its metabolic derivatives. It is suggested that measurements of serum levels of LDH, AM and CHE are particularly helpful in the clinical assessment of pathologies caused by sulfites in allergology.

Guanylate cyclase activity in retina optic nerve and optic chiasm of rats under different illumination conditions

In the present work we have measured the guanylase cyclase activity in soluble fractions from several tissues relevant to the visual response under different illumination conditions. Guanylate cyclase was sensitive to changes of light / dark periods in incubated extract obtained from soluble fractions of retina, optic nerve and optic chiasm. The changes in soluble guanylate cylcase activity found, about 100 fold between dark and light periods in those tissues, indicate a key role for this enzyme. The results showed that light inhibit strongly the soluble retinal guanylate cyclase activity; while it increases the activity of this enzyme in the optic nerve. A generalized photoinhibited response of soluble guanylate cyclase eas observed in all studied tissues in prolonged dark adapted animals. The effect of Na+ 1 and 10 nM, and free Ca++ 28 M and 2.8 MuM on the guanylate cyclase activity was performed in the studied tissues. The enzymatic activity appeared to be inversely related in the retina and optic nerve with regard to the ion exposue, which may involve different ionic control mechanisms. All indicate an active role for the soluble guanylate cyclase in the phototransduction process not only in retina, also in other tissues relevant in the visual response.

Isatin (2,3-dioxoindole): a competitive inhibitor of Na(+)-dependent lysine uptake in rat instestine.

Isatin (2,3-dioxoindole) competitively inhibited (27-40%) Na(+)-dependent L-lysine uptake in rat intestine. The value of Kt was increased from 3.04 mM in control to 5.88 mM in presence of 10 mM isatin. Effect of isatin on the Na(+)-independent amino acid uptake was insignificant (12-18%). The inhibitory constant (Ki) was 2.8 mM under these conditions. The observed inhibition was unaffected by -SH group reacting agents. Isatin (1-10 mM) inhibited Na+, K(+)-ATPase activity in intestine in vitro, the maximum inhibition (66%) being at 10 mM isatin concentration. But the drug had no effect on enzyme activity under in vivo conditions.

Efectos de la insulina sobre la respuesta contractil y la captacion de calcio en aorta de rata / Effect of insulin on contractile response and calcium captation in rat aorta

La insulina afecta mecanismos fisiológicos generales que regulan la presión arterial, y a nivel celular modifica las funciones del endotelio y del mosculo liso vascular, que son determinantes de la resistencia periférica. Describimos los efectos de la preincubación con insulina (40 muU/ml, durante 1-2 hs) sobre la reactividad contráctil de anillos intactos de aorta de rata y sobre la captaci>n de 45Ca2+ en segmentos de aorta de rata hipermeabilizados por tratamiento con EGTA. La preincubación con insulina no afectó las contracciones inducids por 1 muM de NA, ni la relajación de las mismas inducida por 10 mM de cafeína. La respuesta contractil a 1 muM de Ang-II (que en la aorta de rata es independiente de endotelio) fue estimulada por la preincubación con insulina en la fuerza máxima desarrollada y en la velocidad de relajación espontánea de la contracción. La diferencia en la captación de 45Ca2+ en RS entre los segmentos de aorta tratados y no tratados con insulina fue mayor a los 5 minutos con respecto a la medida a los 30 minutos. Se concluye que la preincubación con insulina afecta en forma directa la respuesta mecánica del mosculo liso aórtico estimulado con Ang-II y se propone a la modificación de la actividad del RS como uno de los mecanismos mediante el cual la insulina participa en la regulación del Ca2+ citosólico.

Mecanismos involucrados en el efecto antiarritmico y proarritmico del magnesio / Mechanisms involved in the antiarrhythmic and proarrhythmic effects of magnesium

El objetivo fue analizar en perros, los efectos del MgCl2, y del MgSO4 sobre los mecanismos electrofisiológicos que pudieran vincularse con las acciones antiarrítmicas y proarrítmicas de estas soluciones. Se estudiaron previamente los parámetros farmacocinéticos del MgCl2 y del MgSO4; ambos mostraron que el Mg plasmático disminuye exponencialmente (constante beta de O,118 ñ O,013 h-l), t 1/2 de eliminación de 6,02 ñ O,68 h y una Vda de O,259 ñ O,02lxkg-l. Posteriormente se estudiaron dos grupos de animales - Grupo I: dieta normal. Grupo II A: dieta sin Mg + clortalidona + K y Grupo II B: dieta sin Mg + clortalidona + KCI + MgSO4. Se midieron los electrolitos y las variables electrofisiológicas por medio de estimulación ventricular programada. El grupo I mostró que la administración de MgSO4 endovenoso disminuye el Na, el K y el umbral de fibrilación ventricular (UFV) y prolonga el período refractaria efectivo ventricular (PREV). El MgCl2 no modifica el UFV, pero prolonga el PREV, el A-H, el QTc y el PQ. El MgSO4 aumenta la excreción de K urinario en forma significativamente mayor que el MgCl2. La administración de NaCl no alteró las variables electrofisiológicas pero el NaSO4 disminuyó el K plasmático, sin modificar el UFV. El Grupo II A presentó descenso del K y Mg plasmático, linfocitario y miocárdico, disminución del PREV y del UFV y aumento del QTc. A este grupo se le administro en forma aguda: 1) MgSO4 que provocó mayor descenso del UFV y del K plasmático y aumento del PREV y 2) KCI que aumento el K piasmático y el UFV. El grupo II B no modificó los electrolitos ni las variables electrofisiológicas. Se concluye que los efectos antiarrítmicos observados en clínica por la administración de sales de Mg se deberían probablemente a la prolongación del PREV. Sin embargo, la depleción de K inducida por el MgSO4 puede provocar un descenso del UFV, efecto proarrítmico que se podría evitar utilizando MgCl2.

Efecto de la combinación de benzoato de sodio con lactulosa en la hiperamonemia experimental / Effect of sodium benzoate plus lactulose combination in experimental hyperammonemia

El benzoato de sodio se ha utilizado en el tratamiento de la encefalopatía hepática hiperamonémica con buenos resultados. Con el objeto de investigar si la combinación de benzoato de sodio con un disacárido (lactosa, lactulosa) tiene un efecto aditivo sobre la disminución de amonio plasmático, se estudió el efecto de la combinación de benzoato de sodio con lactulosa en el modelo de anastomosis portocava en la rata, ya que éste es el modelo experimental que produce mayores elevaciones de amonio en sangre. Se utilizaron ratas Wistar de 250-300 g de peso en las que se practicó una anastomosis porto-cava terminolateral. Diez días después de la operación se inició tratamiento experimental por un periodo de siete días, dividiendo a los animales en cuatro grupos: a) solución salina, b) B.S. 500 mg/kg/día, c) lactulosa 4 g/kg/día, d) benzoato de sodio más lactulosa (dosis anotadas). También se incluyeron un grupo de ratas normales y un grupo con operación ficticia como controles. Se tomaron muestras de sangre arterial al final del periodo de estudio y se determinó amonio por el método enzimático. Resultados. El benzoato de sodio y la lactulosa disminuyeron significativamente las concentraciones de amonio plasmático (437ñ50, 433ñ85 ug/dl, respectivamente) en comparación con el grupo control (638 ñ 50 ug/dl, p = 0.05), tal como se esperaba. La combinación de benzoato de sodio con lactulosa produjo una disminución de amonio aún mayor (264 ñ 17 ug/dl, p<0.001), lo cual apoya la existencia de un efecto aditivo entre ambos fármacos. Estos hallazgos parecen reproducirse en la clínica de acuerdo a estudios clínicos preliminares en los que se ha utilizado la combinación de lactosa con benzoato de sodio. Estos resultados sugieren que puede haber un efecto aditivo entre el benzoato de sodio y disacáridos como la lactulosa, lo cual podría aumentar la eficiencia del tratamiento e incluso disminuir la dosis total de medicamentos y aumentar la tolerancia a cada uno de los fármacos. Finalmente, se plantea la posibilidad de emplear otros fármacos derivados del benzoato de sodio

Effect of pH and sodium ions on intestinal uptake of lysine in rats.

Intestinal uptake of lysine in rats progressively decreased with an increase in pH from 5.2 to 8.5, both in the presence and absence of Na+ ions. At pH 5.2 lysine uptake was 30-35% more than that at neutral pH. Na+ activated lysine uptake by 40-50% at pH 5.2 and it was increased to 110-120% at neutral pH. The observed increase in lysine uptake in response to Na+ and H+ gradients was due to enhanced maximal velocity (Vmax), with little change in affinity constant (Kt). Arrhenius analysis revealed a biphasic curve for lysine uptake with transition temperature (Tc) around 20 degrees C (24 degrees C at pH 5.2 in presence of Na+). The energy of activation (Ea) below (16.1-23.4 Kcal/mole) and above (6.7-8.6 Kcal/mole) the Tc was similar at pH 5.2 and 7.0 both in the presence and absence of Na+ ions. The sensitivity of lysine uptake to various inhibitors was also dependent upon pH and Na+ ions.

Effects of Na+ and Ca2+ concentration in cardioplegic and reperfusion solutions on the intracellular Ca2+ of cardiac muscle cells

The removal of Ca2+ from the cardioplegic solutions could cause the danger of inducing a "calcium paradox" during reperfusion. Since intracellular Ca2+ activities are coupled to Na+ activities via Na(+)-Ca2+ exchange, an increase in intracellular Na+ activities during the cardioplegia could cause an abrupt Ca2+ influx when reperfused. To study the effects of Na+ and Ca2+ concentrations in cardioplegic solutions on intracellular Ca2+ activities during the cardioplegia and subsequent recovery period, the membrane potential and intracellular Na+ and Ca2+ activities of guinea pig ventricular papillary were measured. 1) A cardioplegia with low Ca2+ cardioplegic solution significantly decreased the overshoot and duration of the first action potential after cardioplegia, but the changes in action potential configuration were minimized after a cardioplegia with Ca2+ concentration adjusted according to the Na(+)-Ca2+ exchange mechanism. 2) Intracellular Na+ activity was continuously decreased during the cardioplegia, and the intracellular Na+ activity 20 minutes after cardioplegia was the highest with low Ca2+ cardioplegic solution. 3) Intracellular Na+ and Ca2+ activities were continuously decreased during the cardioplegia with Ca2+ concentration adjusted according to the Na(+)-Ca2+ exchange mechanism. 4) During a reperfusion of Tyrode solution after cardioplegia intracellular Na+ and Ca2+ activities were increased. Intracellular Ca2+ activity was increased more rapidly than intracellular Na+ activity. 5) The rate of increase in intracellular Ca2+ activity with reperfusion of Tyrode solution was dependent upon intracellular Na+ activity during cardioplegia, in such a way that the higher the intracellular Na+ activity was, the faster the intracellular Ca2+ activity increased. These data suggest that Na(+)-Ca2+ exchange mechanism may play an important role in the regulation of intracellular Ca2+ activity during recovery after cardioplegia.

Effect of Na+ and Cl-on the velocity of propagation of the spreading depression in chick retina

The chick retina in vitro preparation was used to quantify the effect of Na+ and Cl- on the velocity of propagation of spreading depression (SD). The progressive reduction of chloride concentration in the superfusing Ringer solution, solution, either by partial removal of NaCl or by its partial substitution with isethionate, caused a logarithmic increase in the velocity of propagation of SD. Substituting Tris for Na+ had no appreciable effect on propagation velocity, suggesting that the propagation of the reaction is not necessarily dependent con Na+. Howeverm choline did not substitute for Na+ because it decreased propagation velocity and, at higher concentration, even blocked the spread of the reaction

Effects of dichlorobenzamil, a sodium-calcium exchange inhibitor, on the calcium paradox and the sodium withdrawal contractures of frog atrial muscle

The effects of dichlorobenzamil (DCB), an amiloride derivative and potent inhibitor of Na-Ca exchange in cardiac sarcolemmal vesicles and isolated cardiac myocytes, were investigated in two paradigms involving Na-Ca exchange, namely the Ca2+ paradox and the Na + - withdrawal contractures of frog atrial muscle strips. Pretreatment with DCB (10-100 micronM) inhibited in a dose-dependent manner the contractures elicited by reexposure of the atrial strips to the control Ringer solution after a 5-20 min equilibration with a Ca2 + - free saline (Ca2 + - readmission contractures; Ca2 + paradox). These contracture were not inhibited, however, when DCB was applied after the preparation had been exposed to the Ca2 + - free saline, but before the reexposure to the control Ringer solution. DCB (10-100 micronM) did not inhibit the contractures elicited by Na + - deficient saline (Na + - withdrawal contractures) in atrial strips pretreated or not with acetylstrophantydin. This result suggests that, under our experimental conditions, DCB falied to substantially inhibit the Ca2 + influx mediated by Na-Ca exchange. The duration of the plateu of the action potentials of atrial cells equilibrated with Ca2 + - free saline was reduced from 1,42 ñ 0,27 s to 0,61 ñ 0,13 s by 50 micronM DCB (P<0.001). This was atributed to blockade of Na + currents through modified L-type Ca2 + channels. It is proposed that shortening of the Na + - dependent action potentials can account for the inhibition of the Ca2 + - readmission contractures, because these contractures have a steep dependence on the Na + influx and intracellular Na + accumulation that occurs during the Ca2 + - free period. The results of this study support the conclusion thatDCB has multiple effects on heart muscle, including a potent blockade of Ca2 + channels, and its use as a selective inhibitor of Na-Ca exchange in cellular systems in un unwarranted

Inhibition by dopamine of the neurotransmission in the rat vas deferens

Se investigaron los efectos de agonistas y antagonistas alfa -adrenérgicos y dopaminérgicos sobre los receptores presinápticos de la porción prostática del conducto defrerente de rata. La variable estudiada fue el primer componente (250 ms) de la respuesta motora inducida por estimulación eléctrica de campo (pulso único). Con el objeto de bloquear los sitios de pérdida de las aminas, todos los experimentos se llevaron a cabo en presencia de cocaína 30 micronmol/l e hidrocortisona 28 micronmol/l. Asimismo, se empleó 1-propranolol 0.3 micronmol/l para bloquear los receptores ß -adrenérgiocs. Clonidina, noradrenalina (NA) y dopamina (DA) inhibieron la respuesta motora inducida por la aplicación de un pulso eléctrico. Este efecto fue, para los tres agonistas, dependiente de las concentraciones utilizadas. DA fue 10 y 10**4 veces menos potente que NA y clonidina respectivamente. El agonista selectivo D2, LY 141865, no logró inhibir la respuesta motora inclusive a una alta concentración (30 micronmol/l). Yohimbina (0.1, 0.3 y 1 micronmol/l) antagonizó en forma competitiva el efecto inhibitorio de clonidina, NA y DA, presentando valores similares de -log KB (7.57, 7.68 y 7.09 respectivamente). De manera análoga, idaxozán 0.03 micronmol/l bloqueó el efecto inhibitorio de DA con una potencia similar (- log KB = 7.81) a la de yohimbina. Por otra parte, pimozide 0.21 micronmol/l y Schering 23390 3 micronmol/l antagonizaron el efecto inhibitorio de DA, mostrando una potencia menor que los antagonistas alfa2 -adrenérgicos...

Modificaciones del estado ácido-base del líquido cefalorraquídeo por efecto de la administración de alcalinizantes (bicarbonato de sodio y THAM) / Changes of the acid-base equilibrium of the cerebrospinal fluid by effect of administration of alkaline agents (sodium bicarbonate and THAM)

Cuando se infunde bicarbonato de sodio intravenoso el propósito de corregir la acidosis metabólica se obtienen resultados opuestos en el líquido cefalorraquídeo. La caída del pH en el líquido y, por lo tanto, en el sistema nervioso central, puede ocasionar empeoramiento en el estado de conciencia, modificación de la ventilación y modificación de la perfusión cerebral. Por el contrario, la infusión de THAM - Tris(hidroximetil)aminometano-, modifica en el mismo sentido el estado ácido-base en sangre, líquido cefalorraquídeo y, por lo tanto, en sistema nervioso central, logrando el objetivo de corregir la acidosis, sin introducir secuelas neurológicas. Para demostrar lo expuesto anteriormente, se trabajó con dos grupos de perros que fueron anestesiados y ventilados mecánicamente. A un grupo se le infundió bicarbonato de sodio intravenoso y al otro THAM por la misma vía. Se midieron los siguientes parámetros ácido-base en sangre arterial, venosa y líquido cefalorraquídeo; pH, presión parcial de dióxido de carbono, bicarbonato real, exceso de bases y THAM en el líquido, con un método que desarrollamos para tal fin