The inhibitory role of sympathetic nervous system in the Ca2+-dependent proteolysis of skeletal muscle

Mammalian cells contain several proteolytic systems to carry out the degradative processes and complex regulatory mechanisms to prevent excessive protein breakdown. Among these systems, the Ca2+-activated proteolytic system involves the cysteine proteases denoted calpains, and their inhibitor, calpastatin. Despite the rapid progress in molecular research on calpains and calpastatin, the physiological role and regulatory mechanisms of these proteins remain obscure. Interest in the adrenergic effect on Ca2+-dependent proteolysis has been stimulated by the finding that the administration of β2-agonists induces muscle hypertrophy and prevents the loss of muscle mass in a variety of pathologic conditions in which calpains are activated. This review summarizes evidence indicating that the sympathetic nervous system produces anabolic, protein-sparing effects on skeletal muscle protein metabolism. Studies are reviewed, which indicate that epinephrine secreted by the adrenal medulla and norepinephrine released from adrenergic terminals have inhibitory effects on Ca2+-dependent protein degradation, mainly in oxidative muscles, by increasing calpastatin levels. Evidence is also presented that this antiproteolytic effect, which occurs under both basal conditions and in stress situations, seems to be mediated by β2- and β3-adrenoceptors and cAMP-dependent pathways. The understanding of the precise mechanisms by which catecholamines promote muscle anabolic effects may have therapeutic value for the treatment of muscle-wasting conditions and may enhance muscle growth in farm species for economic and nutritional purposes.

High susceptibility of activated lymphocytes to oxidative stress-induced cell death

The present study provides evidence that activated spleen lymphocytes from Walker 256 tumor bearing rats are more susceptible than controls to tert-butyl hydroperoxide (t-BOOH)-induced necrotic cell death in vitro. The iron chelator and antioxidant deferoxamine, the intracellular Ca2+ chelator BAPTA, the L-type Ca2+ channel antagonist nifedipine or the mitochondrial permeability transition inhibitor cyclosporin A, but not the calcineurin inhibitor FK-506, render control and activated lymphocytes equally resistant to the toxic effects of t-BOOH. Incubation of activated lymphocytes in the presence of t-BOOH resulted in a cyclosporin A-sensitive decrease in mitochondrial membrane potential. These results indicate that the higher cytosolic Ca2+ level in activated lymphocytes increases their susceptibility to oxidative stress-induced cell death in a mechanism involving the participation of mitochondrial permeability transition.

O presente estudo demonstra que linfócitos ativados de baço de ratos portadores do tumor de Walker 256 são mais susceptíveis à morte celular necrótica induzida por tert-butil hidroperóxido (t-BOOH) in vitro quando comparados aos controles. O quelante de ferro e antioxidante deferoxamina, o quelante intracelular de Ca2+ BAPTA, o antagonista de canal de Ca2+ nifedipina ou o inibidor da transição de permeabilidade mitocondrial ciclosporina-A, mas não o inibidor de calcineurina FK-506, inibiram de maneira similar a morte celular induzida por t-BOOH em linfócitos ativados e controles. Os linfócitos ativados apresentaram redução do potencial de membrana mitocondrial induzida por t-BOOH num mecanismo sensível a ciclosporina-A. Nossos resultados indicam que o aumento da concentração de Ca2+ citosólico em linfócitos ativados aumenta a susceptibilidade dos mesmos à morte celular induzida por estresse oxidativo, num mecanismo envolvendo a participação do poro de transição de permeabilidade mitocondrial.

Modulation of gonadotrophin release from pretreated male camel pituitary cell culture with inhibin and both calcium agonist and antagonist

The present study was conducted to identify the modification carried out by both calcium agonist [Cacl2] and antagonist [VHcI] and inhibin like material [OTLP4] on the GnRH stimulated release of FSH and LH from male camel pituitary cell culture collected during breeding and non breeding seasons. The data obtained showed that 100 and 200 ul/ ml of GnRH was able to release both FSH and LH from pituitaries collected during the year. OTLP4 as an inhibin-like preparation was able to block FSH release from the pituitary especially during non breeding season. Calcium chloride pretreatment has a pronounced effect on LH release without any effect on FSH. The higher dose of calcium chloride unable to release LH from pituitaries collected during breeding season and it may be due to the calcium desensitizing effect. VHcl has a potent effect in blocking LH release to the media by all doses used. The blocking effect on FSH was obtained only when VHcI was used in a higher dose. The use of VHcl in the field for treatment of cardiovascular diseases and its effect on male reproduction need further in vivo investigation

Effect of some ions on sperm activation in Brycon henni(Eigenmann 1913)

Spermatozoa in Characid fish remain immobile in seminal plasma and are activated when freed into water where the ionic balance seems to be the main factor starting the activation process. This process was the target of the present study with emphasis on the activation of motility and on motility maintenance over time. The effect of isosmotic solutions was analyzed taking into account the possible combinations of the following ions, Ca2+, K+, Mg2+ and Na+ as well as the effect of channel blocking agents. The parameters measured were cells with motility (per cent), duration of motility (s), plasma membrane potential, and the effect of channel blockers on activation time and on motility. There was an increased motility when the semen was incubated in solutions containing K+ (p<0.05) compared with the control (CaNaMgK solution); the longest duration of motility was attained when the incubation was performed in solutions containing Na+ and Mg2+ (p<0.05). All solutions induced a change in membrane potential detected after 15 s of activation. Blocking K+, Ca2+ and Na+ channels did not alter motility but decreased the activation time (p<0.05). Potassium induced activation at all concentrations up to 105 mM, but motility was drastically decreased at concentrations higher than 140 mM (p<0.05). The conclusion is that interaction of the ionic environment with the cell membrane leads to changes in membrane potential and intracellular signalling that trigger sperm motility in Brycon henni.

Calcium antagonism and the vasorelaxation of the rat aorta induced by rotundifolone

The vasorelaxing activity of rotundifolone (ROT), a major constituent (63.5 percent) of the essential oil of Mentha x villosa, was tested in male Wistar rats (300-350 g). In isolated rat aortic rings, increasing ROT concentrations (0.3, 1, 10, 100, 300, and 500 æg/ml) inhibited the contractile effects of 1 æM phenylephrine and of 80 or 30 mM KCl (IC50 values, reported as means ± SEM = 184 ± 6, 185 ± 3 and 188 ± 19 æg/ml, N = 6, respectively). In aortic rings pre-contracted with 1 æM phenylephrine, the smooth muscle-relaxant activity of ROT was inhibited by removal of the vascular endothelium (IC50 value = 235 ± 7 æg/ml, N = 6). Furthermore, ROT inhibited (pD2 = 6.04, N = 6) the CaCl2-induced contraction in depolarizing medium in a concentration-dependent manner. In Ca2+-free solution, ROT inhibited 1 æM phenylephrine-induced contraction in a concentration-dependent manner and did not modify the phasic contractile response evoked by caffeine (20 mM). In conclusion, in the present study we have shown that ROT produces an endothelium-independent vasorelaxing effect in the rat aorta. The results further indicated that in the rat aorta ROT is able to induce vasorelaxation, at least in part, by inhibiting both: a) voltage-dependent Ca² channels, and b) intracellular Ca2+ release selectively due to inositol 1,4,5-triphosphate activation. Additional studies are required to elucidate the mechanisms underlying ROT-induced relaxation.

Ca2+ -free medium enhances the magnitude of slow peak in compound action potential of frog sciatic nerve in vitro.

The present investigation was carried out to know the effect of Ca2+ on different peaks of compound action potential (CAP) representing the fibers having different conduction velocity. CAP was recorded from a thin bundle of nerve fibers obtained from desheathed frog sciatic nerve. Suction electrodes were used for stimulating and recording purposes. In Ca2+ -free amphibian Ringer, two distinct peaks (Peak-I and Peak-II) were observed. The threshold, conduction velocity (CV), amplitude and duration of Peak-I were 0.32 +/- 0.02 V, 56 +/- 3.0 m/sec, 2.1 +/- 0.2 mV and 0.75 +/- 0.1 ms, respectively. The Peak-II exhibited ten times greater threshold, eight times slower CV, three times lower amplitude and four times greater duration as compared to Peak-I. Addition of 2 mM Ca2+ in the bathing medium did not alter CAP parameters of Peak-I excepting 25% reduction in CV. But, in Peak-II there was 70-75% reduction in area and amplitude. The concentration-attenuation relation of Peak-II to various concentrations of Ca2+ was nonlinear and 50% depression occurred at 0.35 mM of Ca2+. Washing with Ca2+ -free solution with or without Mg2+ (2 mM)/verapamil (10 microM) could not reverse the Ca2+ -induced changes in Peak-II. Washing with Ca2+ -free solution containing EDTA restored 70% of the response. The results indicate that Ca2+ differentially influence fast and slow conducting fibers as the activity of slow conducting fibers is greatly suppressed by external calcium.

Sodium nitroprusside inhibits the intracellular calcium storage and release in rabbit aorta

This study aimed to investigate the possible involvement of the K+ channels by performing concentration response curves of SNP on K+Cl- precontracted aorta. The effect of SNP on the process of Ca2+ release from ic stores by studying its effect on phenylephrine induced contractions in Ca2+ free solution was also studied. The effect of SNP on the process of filling of the ic stores after their emptying by repeated application of phenylephrine in Ca2+ free solution and before the filling period in which the aorta was incubated in normal salt solution containing Ca2+ was evaluated. The possible involvement of endothelium in the SNP induced vasorelaxation was also investigated. The results showed that the relaxant effect of SNP is not endothelium dependent. SNP completely abolished contractions induced by low K+ and partially abolished contractions induced by high K+. SNP produced a significant dose dependent inhibition of the process of filling of the ic stores of Ca2+ and the process of Ca2+ release from these stores

Effect of methoxyverapamil, diltiazem, morphine and their combination on the formation of irreversibly sickled cells: an in vitro study

The effect of methoxyverapamil and diltiazem [calcium antagonists] and morphine [calcium antagonist activity] on the formation of irreversibly sickled cells [ISCs] was investigated. Methoxyverapamil at therapeutic concentration and 10 times that level resulted in a 12% and 21% reduction in the formation of ISCs respectively, which was statistically significant. Diltiazem also produced a significant reduction in ISCs but morphine produced no significant reduction. Combination of these drugs produced a net effect similar to their individual effects. These drugs might be useful in decreasing the intensity of sickling crises and vaso-occlusive events. Thus in vivo trials in patients with sickle-cell disease are suggested

Effects of ovarian hormone tratment on Ca2+-induced contractions and Ca2+-antagonism in the depolarized rat myometrium

The effects of estrogen (E), progesterone (P) and estrogen plus progesterone (E+P) treatment on Cainduced contraction in the KCL-depolarized uterine muscle, and the influences on the Ca2+ antagonism induced by reserpine and verapamil "in vivo" were studied. Uterine muscles from rats in estrus were taken as controls. Uteri from spayed untreated rats showed the same sensivity to Ca2+ as those from estrus rats, but castration decreased maximal contractile tension to Ca2+ and Ca2+ thereshold. P tratment failed to modified the effects of castration on the responses to Ca2+. E or E+P treatments decreased the sensitivity to Ca2+ but only E+P increased slope values and maximal contractile tension. E and E+P increased the potency of verapamil Ca2+ antagonism but none the treatments modified reserpine direct inhibitory effects. The results obtained suggest that alterations on uterine contractility by hormone treatment are the result of complex interactions between both genomic effects on the contractile process as well as nongenomic direct actions of the hormones on Ca2+ membrane permeability.

Tratamiento crónico con nimodipina en el accidente cerebro-vascular (ACV) / Chronic treatment with nimodipina in the brain-vascular stroke

Investigaciones recientes sugieren que las concentraciones elevadas de calcio intracelular puede estar implicadas en la muerte neuronal después de la isquemia. Ventiocho pacientes con accidente cerebro-vascular agudo permanente fueron incluidos en un ensayo clínico prospectivo, bodle ciego y de asignación al azar, para determinar si el tratamiento con el calcio antagonista nimodipina, reduciría su mortalidad y déficit neurológico. A todos los pacientes les fue administrado tratamiento estandarizado. Además, 14 pacientes recibieron diariamente 120mg de nimodipina vía oral dividida en 4 dosis (grupo tratado) durante 180 días. El análisis de la terapéuta se basó en la utilización de tres sistemas de evaluación (Escala Mathew, Barthel y Orgogozo). La comparación de los resultados en el grupo control con aquellos del grupo nimodipina revelaron una diferencia significativa en favor de la nimodipina a los 28 días de tratamiento (Barthel p<0.02; Orgogozo p<0.03) y a los 6 meses (Mathew p<0.05; Barthek p<0.03 y Orgogozo p<0.006). Todos los casos de fallecimiento ocurrieron en los primeros 28 días, completando un total de 10 pacientes, 6 (42.8 por ciento) en el grupo stándar 4 (28.5 por ciento) en el grupo nimodipina. Los efectos colaterales fueron de menor importancia y de ninguna relevancia clínica

Calcium antagonists in the treatment of vestibular disorders / Antagonistas del calcio en el tratamiento de padecimientos vestibulares

Se presenta una revisión de numerosos trabajos estudiando el efecto sobre el síntoma vértigo de dos inhibidores del transporte del calcio, la cinarizina y la flunarizina. Los resultados, todos efectuados con técnica doble ciega y tratamiento estadístico, señalan que ambas sustancias son efectivas y seguras para el tratamiento sintomático del vértigo. Se señala la necesidad de mas estudios clínicos y de laboratorio para precisar mejor las dosis óptimas.

Effect of chemically different calcium antagonists on lipid profile in rats fed on a high fat diet.

Different classes of calcium antagonists, viz. verapamil (diphenylalkylamine), diltiazem (benzothiazepine), nifedipine, felodipine and nimodipine (dihydropyridines), were examined for their effects on lipid profile in rats. Clofibrate was the reference standard. Clofibrate significantly prevented the rise of serum triglycerides and total cholesterol produced by high fat diet and raised antiatherogenic index to 1.6 times than that of high fat diet controls. Of the calcium antagonists studied, felodipine was most effective in preventing the rise of serum triglycerides and total cholesterol in high fat diet fed rats. Felodipine's antiatherogenic index was very high (886%)--much more than that of clofibrate (303%). Diltiazem and nimodipine which also significantly prevented the rise in triglycerides and total cholesterol produced by high fat diet had a moderately beneficial antiatherogenic index similar to that of clofibrate. Though verapamil and nifedipine slightly increased the triglyceride levels, total cholesterol levels were reduced only by verapamil and not by nifedipine. Despite this both these drugs moderately raised antiatherogenic index similar to clofibrate.

Estudio multicéntrico abierto, no comparativo sobre la eficacia y tolerancia de la amlodipina en el tratamiento de la hipertensión arterial primaria leve a moderada / Multicentral opin study, no comparative on the efficacy and tolerance of amlodipina in the treatment arterial principal slight to moderate

El objetivo del presente estudio es evaluar la efectividad y la incidencia de efectos secundarios de la Amlodipina (A) en un rango de dosis de 5 a 10 mg en pacientes hipertensos primarios leves moderados. Se trata de un estudio de 9 semanas de duración que incluyó 38 pacientes, hipertensos primarios, el 54% perteneció al sexo maculino y el 45% al sexo femenino, en un rango de edad de 26 a 72 años y peso entre los 55,6 kg y 88,5 kg. Para la evaluación estadística se aplicó análisis de varianza y "t" de student pareado, estableciéndose un valor de p < 0,05. El ensayo abarcó 3 fases. Fase 1: (1 semana) constituyó el periodo de lavado. Fase II: (4 semanas, de la semana 2 a la semana 5 inclusive) correspondió a la titulación de la dosis. A partir de la semana 2 recibieron 5 mg de Amlodipina O.D., al final de la semana 3 se evaluaron nuevamente las cifras tensionales (c.t.) a objeto de aumentar la dosis a 10 mg en aquellos pacientes cuya presión arterial diastólica (PAD) permaneciera por encima de 90 mmHg, o si la disminución de la PAD era igual o menor de mmHg. Fase III (semana 6,7,8 y 9) período de mantenimiento. Las C.T., frecuencia del pulso (FP) y registro de efectos secundarios se evaluaron durante la duración del estudio, las pruebas de rutina de laboratorio se efectuaron en la primera semana y al final de la semana 9. Al final del período de lavado la presión arterial sistólica (PAS) promedio fue de 163,8 mmHg y la (PAD) 102,2 mmHg, al final de la 3ra. semana disminuyeron a 144,6 mmHg respectivamente lo que fue estadísticamente significativo (p < 0,05). No hubo diferencias significativas en la FP antes y durante el tratamiento. La eficacia clínica estuvo entre excelente y buena en el 88% de los casos, (lográndose el control tensional en la mayoría con 5 mg de A); en el 3% fue moderada y desconocida en el 6%. En cuanto a la tolerancia fue excelente en el 73%, buena 19%, moderada 3%, pobre 3%, desconocida 3%. En los pacientes que presentaron efectos colaterales el 94% fueron leves a moderados y desaparecieron en el trascurso del estudio. Podemos concluir que la A es efectiva y bien tolerada en hipertensión leve y moderada en un rango de dosis de 5 a 10 mg O.D

Influence of calcium on the blood pressure and renal effects of stevioside

The effect of verapamil (V, 0.015 mg/min, iv) or Ca Cl2 (800 mEq/l, 0.025 ml kg-1 min-1,iv) on renal function and mean arterial pressure (MAP) were evaluated in male Wistar rats weighing 280-320 g during treatment with stevioside (S, 16 mg kg-1 h-1, iv). Verapamil administered to 10 rats significantly increased the hypotensive effect of stevioside on MAP (control 124 ñ 0.77; S, 96 ñ 1.50; S+V, 67 ñ 0.70 mm Hg) and fractional sodium excretion (control 0.76 ñ 0.05; S, 1.56 ñ 0.10; S+V, 2.72 ñ 0.25%). Urinary flow, reported as percent glomerular filtration rate (V/GRF), and renal plasma flow (RPF) increased slightly but not significantly during stevioside plus verapamil administration. In contrast, infusion of CaCl2 in 10 rats pretreated with stevioside induced a marked attenuation of MAP (control 119 ñ 1.83; S, 70 ñ 1.12; S ñ CaCl2, 109 ñ 1.60 mmHg) and RPF (control, 16.73 ñ 3.76; S, 34.33 ñ 2.55; S+CaCl2, 17.20 ñ 2.87 ml min-1 Kg-1). The diuresis and natriuresis induced by stevioside were also inhibited by simultaneous administration of CaCl2. These data are consistent with the view that stevioside acts on arterial pressure and renal function as a calcium antagonist, as is the case for verapamil

Efeito do verapamil e do sulfato de estreptomicina sobre a contratilidade cardíaca / Effect of verapamil and streptomycin sulfate on myocardial contractility

O efeito inibitório do verapamil sobre a atividade contráctil do miocárdio, foi comparado com o do sulfato de estreptomicina em coraçäo isolado perfundido de cobaio. O verapamil apresentou um efeito inotrópico negativo, que atingiu o máximo entre 120 a 180 segundos e aos 1.200 segundos a força de contraçäo retornou a níveis normais. O sulfato de estreptomicina apresentou efeito inotrópico negativo máximo aos 30 segundos e a atividade contráctil retornou à níveis normais em aproximadamente 180 a 240 segundos. O efeito inibitório do verapamil diminui com a repetiçäo das injeçöes, enquanto que a repetiçäo das doses de sulfato de estreptomicina näo modifica sua açäo. Ao alterarmos a concentraçäo de cálcio do líquido perfusor observa-se que para o verapamil também foi diminuido o efeito inibitório ao aumentar a concentraçäo de cálcio. O sulfato de estreptomicina produz aumento do efeito inibitório proporcional ao aumento da concentraçäo do íon cálcio

Antagonistas do cálcio e o rim / Calcium antagonists and the kidney

Os antagonistas do cálcio säo usados freqüentemente no tratamento de pacientes com hipertensäo arterial ou doença cardíaca isquêmica. Estes pacientes têm muitas vezes comprometimento renal, daí a importância dos efeitos dos antagonistas do cálcio sobre o rim. Os efeitos dos antagonistas do cálcio sobre a hemodinâmica renal säo variáveis e dependem do estado do paciente e da dose administrada. Os antagonistas do cálcio causam natriurese (eliminaçäo de sódio através da urina) e diurese por um mecanismo que näo e totalmente conhecido, mas que provavelmente näo ocorre devido aos efeitos diretos dos antagonistas do cálcio sobre a hemodinâmica renal. O efeito diurético pode ser útil na medida em que evita o edema que é provocado pela terapia vasodilatadora. Os efeitos dos antagonistas do cálcio sobre a atividade periférica da renina säo imprevisíveis: a renina liberada pode ser afetada diretamente, bem como através de efeitos hemodinâmicos. A farmacocinética dos antagonistas do cálcio pouco se altera na insuficiência renal, uma vez que essas drogas säo metabolizadas no fígado. Os antagonistas do cálcio parecem ser úteis e seguros no tratamento de pacientes hipertensos ou com doença cardíaca isquêmica, coexistindo comprometimento renal

Efecto de la adenosina, teofilina y nifedipina sobre el transporte de calcio en el músculo liso de las vías aéreas / Effect of the adenosine, theophiline and nifedipine on calcium transportation in airway smoth muscle

El músculo liso traqueobronquial es la entidad patobiológica responsable de la broncoconstricción que existe en el asma bronquial y el conocimiento de los eventos que están relacionados a los procesos de contracción y relajación de este músculo es importante para el desarrollo de una terapia racional del asma bronquial. La elevación intracelular de calcio en el músculo liso traqueobronquial está asociada con el inicio de la contracción, mientras que la remoción de este catión del citoplasma está relacionada con el proceso de relajación. Esto último puede ocurrir mediante una remoción activa de este catión a través de la membrana plasmática del músculo liso. La finalidad de este trabajo fue el estudio del transporte activo de calcio en las fracciones de membranas plasmáticas del músculo liso traqueobronquial de bovino en comparación con el del humano. Así mismo, la acción de la adenosina, teofilina y nifedipina sobre el mismo. Para lograr esta meta, se realizó el fraccionamiento sub-celular del músculo liso traqueobronquial de bovino y humano. Las fracciones subcelulares obtenidas mediante centrifugación diferencial en medio isotónico fueron denominados Nuclear (N), Mitocondrial (M), Microsomal (P) y fase soluble (S). Para obtener fracciones altamente puras de membranas plasmáticas se procedió al fraccionamiento de la fracción P, empleando un gradiente discontinuo de sacarosa, lográndose obtener 3 sub-fracciones: P1, P2, P3, de las cuales la fracción P1 resultó la más rica en vesículas derivadas de membranas plasmáticas; demostrada por microscopía electrónica y actividad de 5' Nucleotidasa..