In vitro effect of melatonin on oxygen consumption in liver mitochondria of rats.

OBJECTIVE: To examine the in vitro effect of melatonin on rat mitochondrial liver respiration. METHODS: Oxygen consumption by liver mitochondria was measured polarographically in the presence of one of the following Krebs' cycle substrates: Lsuccinate, DL-3- beta-hydroxybutyrate or L-malate. Respiratory velocities at rest (state 4) and during rapid respiration in the presence of substrate and adenosine diphosphate (state 3) were measured in the presence of 10 (-9)-10(-3) M concentrations of melatonin. RESULTS: In vitro melatonin (10(-7)-10(-3) M) reduced state 3 mitochondrial respiration. Basal, state 4 respiration was not affected by melatonin. Consequently, control respiratory index (i.e., the ratio of state 3 to state 4 respiration) was inhibited by melatonin with a threshold at 10(-7) M concentration. CONCLUSION: The ability of melatonin to curtail acutely the stimulation of oxygen consumption in liver mitochondria may protect the mitochondria from excessive oxidative damage.

A double blind-placebo controlled study on melatonin efficacy to reduce anxiolytic benzodiazepine use in the elderly.

OBJECTIVE: The present double blind-placebo controlled study was carried out to assess whether melatonin (3 mg p.o., fast release form) could be useful to reduce benzodiazepine dosage in old patients with minor sleep disturbance. The possible correlation of urinary excretion of 6-sulphatoxymelatonin (aMT6s) before starting treatment and outcome of treatment was also examined. METHODS: Forty-five patients (36 females, 70.5 +/- 13.1 years old) regularly taking anxiolytic benzodiazepines in low doses were studied. Overall quality of morning freshness, daily alertness, sleep quality, and sleep onset and offset time were assessed from structured clinical interviews and from logs completed by the patients. Patients were randomized to receive either melatonin or placebo for 6 weeks. On day 14 of treatment, benzodiazepine dose was reduced by half and on day 28, it was halted. No significant modifications of sleep or wakefulness were detected after benzodiazepine withdrawal. As compared to basal, there was a general lack of changes in quality of wakefulness or sleep in patients taking melatonin or placebo. Sleep quality of patients taking melatonin during the first two weeks of treatment was significantly lower than that of placebo. Melatonin advanced sleep onset by 27.9 +/- 11.9 min and decreased significantly the variability of sleep onset time (p= 0.03). The urinary concentration of aMT6s prior to the study did not correlate with any parameter examined. CONCLUSION: The present study does not support melatonin efficacy to reduce the use of benzodiazepines in low doses. This contrasted with the demonstrable effectiveness of melatonin to reduce benzodiazepine consumption in insomniac patients when used in hypnotic amounts.

Gender-related differences in urinary 6-sulfatoxymelatonin levels in obese pubertal individuals.

The objective of this study was to measure the urinary excretion of the main melatonin metabolite 6-sulfatoxymelatonin in obese and normal weight (wt) boys and girls. The study included 94 subjects, aged 4-15.7 yr (50 obese and 44 normal wt; 48 boys) classified as: mid-childhood (4-7.99 yr), late-childhood (8-12 yr) and pubertal (10.1-15.7 yr, Tanner II-IV). Normal wt subjects were children with a body mass index (BMI) between the 25th and 75th percentiles, and the group of obese subjects included children whose BMI was above the 97th percentile. A 24-hr urine sample was collected during two intervals: (i) 18:00-08:00 hr, and (ii) 08:00-18:00 hr. Analysis of urinary 6-sulfatoxymelatonin levels was performed by radioimmunoassay. Excretion of 6-sulfatoxymelatonin was expressed as: (i) total amount excreted (microg); (ii) mug excreted per time interval, nocturnal or diurnal; and (iii) the difference between nocturnal and diurnal samples (microg, estimated amplitude). A factorial analysis of variance indicated that nocturnal 6-sulfatoxymelatonin excretion and amplitude were significantly higher in the obese individuals. A significant interaction 'BMI x age' was detected, i.e. the effect of BMI was significant in the pubertal group only. Total, nocturnal and diurnal 6-sulfatoxymelatonin excretion was significantly higher in girls. The increase in 6-sulfatoxymelatonin excretion found in obesity occurred only in boys and at the pubertal age. To what extent this increase in melatonin production contributes to a delayed puberty in some pubertal obese males remains to be established.

Melatonin increases oestradiol-induced bone formation in ovariectomized rats.

To assess the effect of melatonin on bone metabolism in ovariectomized rats, receiving oestradiol therapy or not, melatonin was administered in the drinking water (25 microg/mL water) and oestradiol (10 microg/kg body weight) or vehicle was given subcutaneously 5 days/week for up to 60 days after surgery. Urinary deoxypyridinoline (a marker of bone resorption) and circulating levels of bone alkaline phosphatase activity (a marker of bone formation), as well as serum calcium and phosphorus levels, were measured every 15 days. Bone area (BA), bone mineral content (BMC), bone mineral density (BMD) and total body fat (expressed as 100 g body weight) were measured by dual-energy X-ray absorptiometry at the end of the experiment. Body weight and total body fat were augmented after ovariectomy, and decreased after melatonin or oestradiol treatment. The effect of melatonin on body weight was seen in sham-operated rats only. Ovariectomy augmented, and melatonin or oestradiol lowered, urinary deoxypyridinoline excretion. This effect of melatonin and oestradiol was seen mainly in ovariectomized rats. The efficacy of oestradiol to counteract ovariectomy-induced bone resorption was increased by melatonin. Melatonin or oestradiol lowered serum bone alkaline phosphatase activity. Melatonin inhibition was seen mainly on the increase of bone alkaline phosphatase activity that followed ovariectomy. Serum phosphorus levels decreased after melatonin administration and were augmented after oestradiol injection; overall, melatonin impaired the increase of serum phosphorus caused by oestradiol. Ovariectomy decreased, and oestradiol increased, serum calcium levels while melatonin augmented serum calcium in sham-operated rats only. On day 60 after surgery, BMD and content decreased after ovariectomy and were increased after oestradiol injection. Melatonin augmented BA of spine and BMC of whole of the skeleton and tibia. The highest values observed were those of rats treated concurrently with oestradiol and melatonin. The present results indicate that: (i) melatonin treatment restrained bone remodelling after ovariectomy; (ii) the effect of melatonin required adequate concentrations of oestradiol; (iii) melatonin augmented oestradiol effects on bone in ovariectomized rats; (iv) a counter-regulation by melatonin of the increase in body fat caused by ovariectomy was uncovered. The melatonin doses employed were pharmacological in terms of circulating melatonin levels but not necessarily for some other fluids or tissues.

A multifactorial approach employing melatonin to accelerate resynchronization of sleep-wake cycle after a 12 time-zone westerly transmeridian flight in elite soccer athletes.

Rapid transmeridian translocation through multiple time zones has a negative impact on athletic performance. The aim of the present study was to test the timely use of three factors (melatonin treatment, exposure to light, physical exercise) to hasten the resynchronization of a group of elite sports competitors and their coaches to a westerly transmeridian flight comprising of 12 time-zones. Twenty-two male subjects were included in the study. They were professional soccer players and their coaches who travelled to Tokyo to play the final game of the Intercontinental Coup. The day prior to departure, urine was collected from each subject from 18:00 to 06:00 hrs to measure the melatonin metabolite 6-sulphatoxymelatonin. Participants were asked to complete sleep log diaries from day 0 (preflight) to the day before returning to Buenos Aires (day 8). All subjects received 3 mg of melatonin p.o. daily at expected bedtime at Tokyo immediately after leaving Buenos Aires. Upon arrival at Tokyo the subjects performed a daily physical exercise routine outdoors at two restricted times of the day (from 08:00 to 11:00 hrs in the morning and from 13:00 to 16:00 hrs in the afternoon). Exposure to sunlight or physical exercise at other times of the day was avoided. Except for the number of awakenings (which increased on days 1 and 3) and sleep latency (which decreased on days 2, 6 and 8), there was an absence of significant changes in subjective sleep parameters as compared with preflight assessment. Sleep quality and morning alertness at Tokyo correlated significantly with preflight 6-sulphatoxymelatonin excretion. Mean resynchronization rate of sleep-wake cycle to the 12 hr-time shift was 2.13 +/- 0.88 days, significantly different from the minimal resynchronization rate of 6 days expected after a 12-time-zones flight. The results indicate that the combination of melatonin treatment, an appropriate environmental light schedule and timely applied physical exercise can be useful to help elite athletes to overcome the consequences of jet lag.

Vascular reactivity in diabetic rats: effect of melatonin.

The aim of the present study was to evaluate the in vitro contractile response of rat aorta in mild and severe type I diabetes and the effect of melatonin on it. Aortic rings were obtained from male Wistar rats injected with streptozotocin 8-12 wks earlier. Rats were divided into three groups: non-diabetic rats (NDR), mildly diabetic rats (MDR) and severely diabetic rats (SDR). Dose-response curves for acetylcholine-induced, endothelium-related relaxation of aortic rings (after previous exposure to phenylephrine) and for serotonin-induced vasoconstriction were conducted in the presence or absence of 10-5 mol/L melatonin. This protocol was repeated with rings preincubated in a high glucose solution (44 mmol/L). The contractile response to phenylephrine decreased in SDR, an effect counteracted by preincubation with high glucose. Melatonin decreased phenylephrine-induced vasoconstriction in MDR and counteracted the effect of high glucose in SDR. Acetylcholine-evoked relaxation decreased significantly after exposure to a high glucose in SDR, this effect being counteracted by melatonin. Serotonin-induced vasoconstriction decreased in SDR and augmented in MDR, but only after exposure to high glucose. Melatonin reduced the maximal tension of aortic contraction after serotonin in MDR, both under basal conditions and after preincubation in a high glucose solution. The results support the existence of differences in vasomotor responses as a function of the diabetes state and of an improvement of contractile performance in diabetic rats after exposure to melatonin at a pharmacological concentration (in terms of circulating melatonin levels but not necessarily for some other fluids or tissues).

Low urinary 6-sulfatoxymelatonin levels in patients with severe congestive heart failure.

OBJECTIVE: To assess urinary 6-sulfatoxymelatonin excretion in patients admitted to the hospital because of congestive heart failure (CHF). METHODS: Urinary 6-sulfatoxymelatonin was measured by a specific radioimmunoassay in 33 hospitalized patients with CHF and in 146 healthy ambulatory volunteers. Individuals with hepatic or renal failure were excluded from the sample. Data were analyzed by the Mann-Whitney test and regression analysis. RESULTS: 6-Sulfatoxymelatonin levels were significantly lower in CHF patients than controls (median 2.6 vs 6.02 microg, p < 0.0001). This decrease was observed regardless of beta-adrenergic blocker or benzodiazepine medication. A significant decrease in 6-sulfatoxymelatonin excretion occurred with age. There were no significant differences in urinary 6-sulfatoxymelatonin levels between chronic and acute CHF patients. CONCLUSIONS: The results suggest that circulating melatonin levels are low in patients with CHF. Such a decrease may precede aggravation of heart failure.

Los errores... una forma de aprender / Mistakes... a form to learning

El artículo fundamenta la conveniencia de aplicar una perspectiva analítica en el procesamiento del error. La misma se iniciaría con la autoevaluación y terminaría con el análisis colectivo del grupo sometido al riesgo de errar. El tratamiento reflexivo permitiría controlar los condicionantes del error, convirtiéndolo en una experiencia de aprendizaje. La autora propone formalizar el proceso en una actividad programada del equipo de trabajo, con sesiones periódicas destinadas a realizar la Clínica del error (AU)

Los errores... una forma de aprender / Mistakes... a form to learning

El artículo fundamenta la conveniencia de aplicar una perspectiva analítica en el procesamiento del error. La misma se iniciaría con la autoevaluación y terminaría con el análisis colectivo del grupo sometido al riesgo de errar. El tratamiento reflexivo permitiría controlar los condicionantes del error, convirtiéndolo en una experiencia de aprendizaje. La autora propone formalizar el proceso en una actividad programada del equipo de trabajo, con sesiones periódicas destinadas a realizar la Clínica del error

Papel de los mediadores vasoactivos en la fisiopatología de la hipertensión portal / Role of vasoactive mediators in the physiopathology of portal hypertension

Se evalúa el papel de los mediadores vasoactivos en la fisiopatología de la hipertensión portal, ya sea promoviendo un aumento de la resistencia vascular en la circulación intrahepática y/o portocolateral, o estimulando una vasodilatación esplácnica con un paralelo incremento del flujo sanguíneo portocolateral. En la actualidad se conoce que el factor inicial de la hipertensión portal es el aumento de la resistencia vascular intrahepática, ocasionada por los cambios morfológicos del hígado asociados a la cirrosis. Sin embargo, existen en la actualidad múltiples evidencias sobre la participación de un componente activo, células con propiedades contráctiles, que puede ser modulado por mediadores vasoactivos como la endotelina y el óxido nítrico. Por otra parte, se conoce actualmente que el aumento del flujo sanguíneo portal mantiene y agrava el síndrome de hipertensión portal. Este aumento del flujo portal es el resultado de una vasodilatación esplácnica ocasionada tanto por el aumento de sustancias vasodilatadoras como por una hiporreactividad a vasoconstrictores endógenos. En este sentido, estudios clínicos y experimentales han demostrado que sustancias como el glucagon, la prostaciclina y más recientemente el óxido nítrico, pueden jugar un papel importante en ambos mecanismos de vasodilatación esplácnica

Papel de los mediadores vasoactivos en la fisiopatología de la hipertensión portal / Role of vasoactive mediators in the physiopathology of portal hypertension

Se evalúa el papel de los mediadores vasoactivos en la fisiopatología de la hipertensión portal, ya sea promoviendo un aumento de la resistencia vascular en la circulación intrahepática y/o portocolateral, o estimulando una vasodilatación esplácnica con un paralelo incremento del flujo sanguíneo portocolateral. En la actualidad se conoce que el factor inicial de la hipertensión portal es el aumento de la resistencia vascular intrahepática, ocasionada por los cambios morfológicos del hígado asociados a la cirrosis. Sin embargo, existen en la actualidad múltiples evidencias sobre la participación de un componente activo, células con propiedades contráctiles, que puede ser modulado por mediadores vasoactivos como la endotelina y el óxido nítrico. Por otra parte, se conoce actualmente que el aumento del flujo sanguíneo portal mantiene y agrava el síndrome de hipertensión portal. Este aumento del flujo portal es el resultado de una vasodilatación esplácnica ocasionada tanto por el aumento de sustancias vasodilatadoras como por una hiporreactividad a vasoconstrictores endógenos. En este sentido, estudios clínicos y experimentales han demostrado que sustancias como el glucagon, la prostaciclina y más recientemente el óxido nítrico, pueden jugar un papel importante en ambos mecanismos de vasodilatación esplácnica

La dexametasona, un inhibidor de la expresion de la oxido nitrico sintasa inducible, no modifica el estado hiperdinamico en ratas cirroticas / Dexamethasone, an inhibitor of the expression of the inducible nitric oxide synthase, does not modify the hyperdynamic state in cirrhotic rats

El aumento de la producción de óxido nítrico juega un papel importante en la fisiopatología de la cir- culación hiperdinámica asociada a la hipertensión portal. El probable mecanismo por el cual se produce este aumento no se encuentra aún bien definido. Con el objetivo de evaluar si la isoforma inducible es la responsable de estos cambios hemodinámicos, hemos estudiado el efecto de la administración de dexametasona, un inhibidor de la expresión de la óxido nítrico sintasa II, en ratas cirróticas tras la ligadura y sección del colédoco. Se determinaron los diferentes parámetros hemodinámicos sistémicos y esplácnicos, mediante la técnica de microesferas radiactivas, luego de la administración de dexametasona (3 mg/kg/día durante 3 días, ip) o su vehículo. En los animales cirróticos el efecto glucocorticoideo se puso de manifiesto a través de una disminución significativa en la ganancia de peso corporal y un moderado aumento, pero no significativo, de la presión arterial media. La administración de dexametasona no se asoció a cambios significativos de la resistencia vascular sistémica y esplácnica como así tampoco del flujo sanguíneo portal y presión portal. Similares resultados se observaron en el grupo de animales utilizados como controles. Se detectaron niveles significativamente más elevados de endotoxina en sangre portal y sistémica en 5 de 6 animales cirróticos. Nuestros resultados muestran que la administración de dexametasona no modifica los parámetros hemodinámicos sistémicos y esplácnicos en ratas cirróticas y endotoxémicas sugiriendo que la estimulación de la sintasa inducible no juega un papel importante en el aumento de la síntesis de óxido nítrico en la cirrosis.

La dexametasona, un inhibidor de la expresion de la oxido nitrico sintasa inducible, no modifica el estado hiperdinamico en ratas cirroticas / Dexamethasone, an inhibitor of the expression of the inducible nitric oxide synthase, does not modify the hyperdynamic state in cirrhotic rats

El aumento de la producción de óxido nítrico juega un papel importante en la fisiopatología de la cir- culación hiperdinámica asociada a la hipertensión portal. El probable mecanismo por el cual se produce este aumento no se encuentra aún bien definido. Con el objetivo de evaluar si la isoforma inducible es la responsable de estos cambios hemodinámicos, hemos estudiado el efecto de la administración de dexametasona, un inhibidor de la expresión de la óxido nítrico sintasa II, en ratas cirróticas tras la ligadura y sección del colédoco. Se determinaron los diferentes parámetros hemodinámicos sistémicos y esplácnicos, mediante la técnica de microesferas radiactivas, luego de la administración de dexametasona (3 mg/kg/día durante 3 días, ip) o su vehículo. En los animales cirróticos el efecto glucocorticoideo se puso de manifiesto a través de una disminución significativa en la ganancia de peso corporal y un moderado aumento, pero no significativo, de la presión arterial media. La administración de dexametasona no se asoció a cambios significativos de la resistencia vascular sistémica y esplácnica como así tampoco del flujo sanguíneo portal y presión portal. Similares resultados se observaron en el grupo de animales utilizados como controles. Se detectaron niveles significativamente más elevados de endotoxina en sangre portal y sistémica en 5 de 6 animales cirróticos. Nuestros resultados muestran que la administración de dexametasona no modifica los parámetros hemodinámicos sistémicos y esplácnicos en ratas cirróticas y endotoxémicas sugiriendo que la estimulación de la sintasa inducible no juega un papel importante en el aumento de la síntesis de óxido nítrico en la cirrosis. (AU)

Papel del óxido nítrico en las alteraciones de la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal / Role of nitric oxide in the alterations of the systemic and splanchnic hemodynamics in a experimental model of portal hypertension

Se evaluó el efecto de la Nw-Nitro-L-arginina (L-NNA), un inhibidor específico de la síntesis de óxido nítrico, sobre la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal (ligadura parcial de la vena porta). La administración de L-NNA en los animales con hipertensión portal ocasionó un aumento significativo de la presión arterial media, una reducción del gasto cardíaco y un aumento de la resistencia vascular periférica. A nível de la hemodinámica esplácnica la L-NNA ocasionó un marcado incremento de la resistencia vascular esplácnica con la consecuente disminución del flujo sanguíneo portal. No se observaron cambios singnificativos en la presión portal. El pretratamiento con L-arginina inhibió los efectos hemodinámicos de la L-NNA. Similares niveles plasmáticos de endotoxina se detectaron en ambos grupos de animales. En el grupo control La L-NNA produjo un aumento de la presión arterial media; sin embargo, y a diferencia de lo observado en los animales on hipertensión portal, la administración de L-NNA no se acompaño de cambios significativos en el gasto cardíaco, flujo sanguíneo portal ni resistencia vascular esplácnica. Nuestros resultados sugieren que las alteraciones, tanto de la hemodinámica sistémica como esplácnica, asociadas a la hipertensión portal, pueden ser atenuadas mediante la administración de L-NNA. Asimismo, el aumento de la síntesis de óxido nítrico puede jugar un papel importante en la fisiopatogenia de estos trastornos hemodinámicos

Hemostatic and hemodynamic effects of vasopressin analogue DDAVP in patients with cirrhosis

Desmopressin (DDAVP), a synthetic analogue of vasopressin, has been shown to improve the bleending time in patients with cirrhosis. The duration of this effect and the hemodynamic changes associated with DDAVP have been studied so far. To evaluate these issues, 14 cirrhotics with portal hypertension were studied in basal conditions and after DDAVP (0.3 uk/kg). In 8 patients, hemostatic tests were done at basal conditions and 1,3,6 and 24 hs after drug administration. In the remaining 6 patients, mean arterial pressure, cardiac output, portal and femoral blood flows were evaluated. Hemodynamic parameters were measured by Doppler ultrasound. DDAVP caused a marked decrease in bleeding time at 1,3,6 and 24 hs (14+9 vs 8+3, 7+4, 6+4 and 8+4 min, respectively); the decrease was maximal and statiscally significant at 6 hs (55+15 percent, p<0.02) after DDAVP infusion. Bleeding time reduction was observed in every patient studied. In the hemodynamic study, DDAVP caused a mild but significant decrease in mean arterial pressure (12+8 percent, p<0.05); no significant changes were observed in the rest of hemodynamic parameters studied. These findings show that DDAVP can be used to shorten the bleeding time for a period of at least 24 hs in patients with cirrhosis, without deleterious hemodynamic effects. This beneficial effect may be of potential relevance in the medical management of patients with chronic liver diseases.

Atrial natriuretic factor in two kidney - two clip renovascular hypertension in the rat

Hig levels of circulating atrial natriuretic factor (ANF) have been reported in several physiopathologic conditions like hypertension, heart and renal failure, pregnancy and high sodium intake. Nevertheless, neither relationships with water-sodium space regulation nor the role of an ANF vascular relaxant effect have been yet defined. The aim of present experiments was to characterize the contribution of circulating ANF and its vascular relaxing effects in the two kidney-two clip (2K2C) experimental model of renovascular hypertension. Complementary, plasma metabolites nitrite/nitrate of nitric oxide (NO) was examined because of mediation for both (NO an ANF) through cGMP. The results showed (two-four weeks after surgery): indirect sistolic blood pressure (mmHg), 186 + 4 in HT and 122 + 1 in SH (p<0.001); a significant increase of plasma ANF (fmol/ml) in HT (n = 7, 1221 + 253) vs. SH (n = 9, 476 + 82; p < 0.02). Nitrate/nitrite plasma concentrations (mumol/l) were mpt different between SH and. The relaxant effect of ANF (10(-9), 10(-8) and 10(-7) M) on phenylephrine (3,5 x 10(-6) M) contracted rings from HT rats was smaller than SH rats (10(-8) M, p < 0.05). Contractions to phorbol 12, 13-dibutyrate (seven weeks after surgery) were significantly higher in rings from HT rats (p < 0.001). We conclude: 1) in addition to decreased granularity in atrial myocardiocytes, high circulating values of ANF here described suggest an increased turnover of the peptide in 2K2C hypertensive rats; 2) lower significant vascular relaxant effects in HT rats would indicate down regulation of ANF receptors in this model; the latter would derive from high plasma ANF concentration and, tentatively, because of greater activity of protein kinase C in the vascular wall; 39 similar values of plasma nitrite/nitrate in SH and HT rats would indicate a comparable NO circulating availability in both groups.

Atrial natriuretic factor in two kidney - two clip renovascular hypertension in the rat

Hig levels of circulating atrial natriuretic factor (ANF) have been reported in several physiopathologic conditions like hypertension, heart and renal failure, pregnancy and high sodium intake. Nevertheless, neither relationships with water-sodium space regulation nor the role of an ANF vascular relaxant effect have been yet defined. The aim of present experiments was to characterize the contribution of circulating ANF and its vascular relaxing effects in the two kidney-two clip (2K2C) experimental model of renovascular hypertension. Complementary, plasma metabolites nitrite/nitrate of nitric oxide (NO) was examined because of mediation for both (NO an ANF) through cGMP. The results showed (two-four weeks after surgery): indirect sistolic blood pressure (mmHg), 186 + 4 in HT and 122 + 1 in SH (p<0.001); a significant increase of plasma ANF (fmol/ml) in HT (n = 7, 1221 + 253) vs. SH (n = 9, 476 + 82; p < 0.02). Nitrate/nitrite plasma concentrations (mumol/l) were mpt different between SH and. The relaxant effect of ANF (10(-9), 10(-8) and 10(-7) M) on phenylephrine (3,5 x 10(-6) M) contracted rings from HT rats was smaller than SH rats (10(-8) M, p < 0.05). Contractions to phorbol 12, 13-dibutyrate (seven weeks after surgery) were significantly higher in rings from HT rats (p < 0.001). We conclude: 1) in addition to decreased granularity in atrial myocardiocytes, high circulating values of ANF here described suggest an increased turnover of the peptide in 2K2C hypertensive rats; 2) lower significant vascular relaxant effects in HT rats would indicate down regulation of ANF receptors in this model; the latter would derive from high plasma ANF concentration and, tentatively, because of greater activity of protein kinase C in the vascular wall; 39 similar values of plasma nitrite/nitrate in SH and HT rats would indicate a comparable NO circulating availability in both groups. (AU)

Hemostatic and hemodynamic effects of vasopressin analogue DDAVP in patients with cirrhosis

Desmopressin (DDAVP), a synthetic analogue of vasopressin, has been shown to improve the bleending time in patients with cirrhosis. The duration of this effect and the hemodynamic changes associated with DDAVP have been studied so far. To evaluate these issues, 14 cirrhotics with portal hypertension were studied in basal conditions and after DDAVP (0.3 uk/kg). In 8 patients, hemostatic tests were done at basal conditions and 1,3,6 and 24 hs after drug administration. In the remaining 6 patients, mean arterial pressure, cardiac output, portal and femoral blood flows were evaluated. Hemodynamic parameters were measured by Doppler ultrasound. DDAVP caused a marked decrease in bleeding time at 1,3,6 and 24 hs (14+9 vs 8+3, 7+4, 6+4 and 8+4 min, respectively); the decrease was maximal and statiscally significant at 6 hs (55+15 percent, p<0.02) after DDAVP infusion. Bleeding time reduction was observed in every patient studied. In the hemodynamic study, DDAVP caused a mild but significant decrease in mean arterial pressure (12+8 percent, p<0.05); no significant changes were observed in the rest of hemodynamic parameters studied. These findings show that DDAVP can be used to shorten the bleeding time for a period of at least 24 hs in patients with cirrhosis, without deleterious hemodynamic effects. This beneficial effect may be of potential relevance in the medical management of patients with chronic liver diseases. (AU)

Papel del óxido nítrico en las alteraciones de la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal / Role of nitric oxide in the alterations of the systemic and splanchnic hemodynamics in a experimental model of portal hypertension

Se evaluó el efecto de la Nw-Nitro-L-arginina (L-NNA), un inhibidor específico de la síntesis de óxido nítrico, sobre la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal (ligadura parcial de la vena porta). La administración de L-NNA en los animales con hipertensión portal ocasionó un aumento significativo de la presión arterial media, una reducción del gasto cardíaco y un aumento de la resistencia vascular periférica. A nível de la hemodinámica esplácnica la L-NNA ocasionó un marcado incremento de la resistencia vascular esplácnica con la consecuente disminución del flujo sanguíneo portal. No se observaron cambios singnificativos en la presión portal. El pretratamiento con L-arginina inhibió los efectos hemodinámicos de la L-NNA. Similares niveles plasmáticos de endotoxina se detectaron en ambos grupos de animales. En el grupo control La L-NNA produjo un aumento de la presión arterial media; sin embargo, y a diferencia de lo observado en los animales on hipertensión portal, la administración de L-NNA no se acompaño de cambios significativos en el gasto cardíaco, flujo sanguíneo portal ni resistencia vascular esplácnica. Nuestros resultados sugieren que las alteraciones, tanto de la hemodinámica sistémica como esplácnica, asociadas a la hipertensión portal, pueden ser atenuadas mediante la administración de L-NNA. Asimismo, el aumento de la síntesis de óxido nítrico puede jugar un papel importante en la fisiopatogenia de estos trastornos hemodinámicos (AU)