Anti-obesity properties of the strain Bifidobacterium animalis subsp. lactis CECT 8145 in Zücker fatty rats.

We evaluated the effect of oral administration of Bifidobacterium animalis subsp. lactis CECT 8145 strain in Zücker fatty rats. The Zücker fatty rats were randomly divided into two groups (n=10 each) and administered either B. animalis subsp. lactis CECT 8145 (1010 cfu/day) suspended in skim milk, or skim milk alone (control group). Each treatment was administered in drinking bottles from week 5 until week 17 of age. A lean Zücker rat group (standard group) was included to provide normal values for the Zücker strain. This group was administered skim milk in the drinking bottle for the same experimental period as Zücker fatty rats. Body weight gain was greater in the fatty control group than in the fatty rats treated daily with B. animalis subsp. lactis CECT 8145. Furthermore, dry and liquid food intake significantly decreased in the treated Zücker fatty group and these rats also showed decreased plasma ghrelin levels as compared with the Zücker fatty control group. B. animalis subsp. lactis CECT 8145 intake also decreased plasma tumour necrosis factor-α (a proinflammatory cytokine) and plasma malondialdehyde (a biomarker of oxidative stress). Moreover, the ratio plasma total cholesterol/plasma cholesterol transported by high-density lipoproteins, considered as an index for cardiovascular disease, also significantly decreased in the Zücker fatty rats treated with B. animalis subsp. lactis CECT 8145. By contrast, this bacterial strain significantly increased plasma adiponectin (an insulin-sensitising adipokine), but did not produce significant effects on triglyceride levels or glucose metabolism biomarkers. Although further research is required to confirm B. animalis subsp. lactis CECT 8145 is an efficient anti-obesity treatment in humans, the results obtained in this study are promising and point to the health and anti-obesity properties of this bacterial strain.

Dietary fiber and blood pressure control.

In the past few years, new strategies to control blood pressure levels are emerging by developing new bioactive components of foods. Fiber has been linked to the prevention of a number of cardiovascular diseases and disorders. ß-Glucan, the main soluble fiber component in oat grains, was initially linked to a reduction in plasma cholesterol. Several studies have shown afterward that dietary fiber may also improve glycaemia, insulin resistance and weight loss. The effect of dietary fiber on arterial blood pressure has been the subject of far fewer studies than its effect on the above-mentioned variables, but research has already shown that fiber intake can decrease arterial blood pressure in hypertensive rats. Moreover, certain fibers can improve arterial blood pressure when administered to hypertensive and pre-hypertensive subjects. The present review summarizes all those studies which attempt to establish the antihypertensive effects of dietary fiber, as well as its effect on other cardiovascular risk factors.

Nitric oxide mediates the antihypertensive and vascular relaxing effects of a soluble cocoa fiber product in spontaneously hypertensive rats.

The involvement of endothelial-relaxing factors on the vascular and antihypertensive effects of a cocoa fiber product (CFP) obtained from cocoa husks was studied. We carried out in vitro experiments with aorta rings from untreated spontaneously hypertensive rats (SHR) and in vivo experiments with SHR. CFP did not relax the endothelium denuded aorta rings and N(W)-nitro-l-arginine methyl ester (l-NAME) partially blocked the vascular relaxing and antihypertensive effects of CFP. Nevertheless, indomethacin did not modify these effects. Nitric oxide mediates therefore the antihypertensive and aorta relaxing effects of CFP in SHR.

[The polyphenols, naturally occurring compounds with beneficial effects on cardiovascular disease]. / Los polifenoles, compuestos de origen natural con efectos saludables sobre el sistema cardiovascular.

In recent years, a number of studies have endorsed the beneficial effects of polyphenols intake on health, especially on the cardiovascular system. This is important since cardiovascular diseases are the main death cause worldwide. The effects of polyphenols are mainly due to their antioxidant properties. These compounds present vasodilating effects, and they can improve the lipid profile and lessen the oxidation of low-density lipoproteins (LDL). They show clear antiinflammatory effects and they can modulate the apoptotic pathways in the vascular endothelium. This review defines from the structural viewpoint the different groups of polyphenols that may occur in vegetables, and updates the knowledge on their bioavailability. Some of the recent studies establishing their beneficial properties at a cardiovascular level are also included.

Los polifenoles, compuestos de origen natural con efectos saludables sobre el sistema cardiovascular / The polyphenols, naturally occurring compounds with beneficial effects

En los últimos años numerosos estudios han avalado los efectos beneficiosos de la ingesta de polifenoles sobre la salud, especialmente sobre el sistema cardiovascular. Esto es importante, porque las enfermedades cardiovasculares son la principal causa de muerte en el mundo. Los efectos de los polifenoles son fundamentalmente consecuencia de sus propiedades antioxidantes. Estos compuestos presentan efectos vasodilatadores, son capaces además de mejorar el perfil lipídico y atenúan la oxidación de las lipoproteínas de baja densidad (LDL). Presentan claros efectos antiinflamatorios y estos compuestos son a su vez capaces de modular los procesos de apoptosis en el endotelio vascular. Esta revisión define desde el punto de vista estructural, los distintos grupos de polifenoles que pueden formarse en los vegetales y actualiza los conocimientos sobre su biodisponibilidad. En ella se recopilan asimismo algunos de los estudios recientes que establecen sus propiedades beneficiosas a nivel cardiovascular (AU)

In recent years, a number of studies have endorsed the beneficial effects of polyphenols intake on health, especially on the cardiovascular system. This is important since cardiovascular diseases are the main death cause worldwide. The effects of polyphenols are mainly due to their antioxidant properties. These compounds present vasodilating effects, and they can improve the lipid profile and lessen the oxidation of low-density lipoproteins(LDL). They show clear anti inflammatory effects and they can modulate the apoptotic pathways in the vascular endothelium. This review defines from the structural viewpoint the different groups of polyphenols that may occur in vegetables, and updates the knowledge on their bioavailability. Some of the recent studies establishing their beneficial properties at a cardiovascular level are also included (AU)

Effect of a cocoa polyphenol extract in spontaneously hypertensive rats.

In this study, we evaluated the short-term effect of a cocoa polyphenol extract (CPE), in spontaneously hypertensive rats (SHR). Male 17-22-week-old SHR were administered by intragastric gavage water, 50 mg kg(-1) Captopril or CPE at different doses (13, 26, 80 and 160 mg kg(-1)). The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded by the tail cuff method before the administration and also 2, 4, 6, 8, 24, 48 and 72 h post-administration. Highly significant decreases in the SBP and in the DBP were observed when captopril or CPE was administered to SHR. The cocoa extract produced a dose dependent effect in the SBP of the SHR up to the dose of 80 mg kg(-1). Nevertheless this dose of CPE did not decrease the arterial blood pressure in the normotensive Wistar Kyoto rats. The decrease in the SBP caused by 80 mg kg(-1) of CPE in the SHR (-39.1 ± 3.7 mm Hg) was maximum 6 h post-administration, and the initial values of SBP were recovered 72 h post-administration of this extract. Paradoxically, 160 mg kg(-1) of the cocoa extract caused a decreased antihypertensive effect than lower doses of CPE. In addition, the decrease in DBP was always more accentuated when the dose of CPE administered was lower. Our results suggest that CPE may be used as a functional food ingredient with beneficial effects for controlling arterial blood pressure.

Evidence that nitric oxide mediates the blood pressure lowering effect of a polyphenol-rich cocoa powder in spontaneously hypertensive rats.

The involvement of endothelial-relaxing factors on the antihypertensive effect of a polyphenol-rich cocoa powder named CocoanOX (CCX) was studied. Thirty 17-20-week-old male spontaneously hypertensive rats (SHR), weighing 314 ± 3g were used. They were divided into two groups of 15 animals, that were respectively administered by gastric intubation distilled water or 300 mg/kg CCX dissolved in distilled water, between 9 am and 10 am. 2h after the oral administration, 5 of the animals in each group were intraperitoneally administered 1 ml saline. The remaining rats in both groups were divided into another two groups of 5 animals that were respectively administered 30 mg/kg Nw-nitro-L-arginine methyl ester (L-NAME) dissolved in 1 ml of saline or 5 mg/kg indomethacin also dissolved in 1 ml of saline by the same procedure. Systolic blood pressure (SBP) was recorded in the rats by the tail cuff method before the initial oral administration and also 4h after this administration. CCX caused a significant decrease in SBP (-49.5 ± 4.9 mmHg; p<0.05). L-NAME caused a clear increase in SBP in the rats (+16.2 ± 4.3 mmHg; p<0.05), and the effect of CCX was not observed in the SHR that were treated with L-NAME (+4.1 ± 1.7 mmHg; p<0.05). Nevertheless, indomethacin treatment did not modify SBP in the SHR and this compound failed to modify the antihypertensive effect of CCX in these animals. In conclusion, this study proves the participation of NO in the antihypertensive effect of CCX in the SHR strain. When CCX is administered, the synthesis, or the bioavailability, of this endothelial factor could increase, but other mechanisms may also participate in the antihypertensive effect of this cocoa powder. In any case, further investigation should be carried out to characterize the signalling pathways involved in the antihypertensive effect of CCX.

Arterial blood pressure and aortic responses in obese, age-grouped Zucker rats.

Endothelial dysfunction is one of the many proposed mechanisms of hypertension and it may justify, at least in part, the increased blood pressure of hypertensive subjects. Nevertheless, the exact mechanisms involved in the hypertensive condition of obese Zucker rats are unclear. In this study, we measured the arterial blood pressure (tail cuff method) of four groups of seven, female, obese Zucker rats each. The rats of groups 1-4 were 9-12, 15-18, 21-24 and 27-30 weeks old respectively. We also evaluated the responses of aortic rings to KCl, methoxamine and acetylcholine, in these animals. Aortic rings were successively exposed to 80 mM KCl and to methoxamine (10(-8)-10(-5) M). The endothelium-dependent relaxation to acetylcholine (10(-9)-10(-5) M) was also established in the methoxamine-precontracted tissue (precontraction close to 80% of the maximum effect of methoxamine). A clear increase in the arterial blood pressure was observed when the age of these animals increased. The contractile responses to KCl and methoxamine were lower in the aortic rings of rats with increased arterial blood pressure. The response to acetylcholine was lower in the rings from 15-18, 21-24 and 27-30 weeks old rats, than in the younger groups. In conclusion, obese Zucker rats develop hypertension and endothelial dysfunction. Nevertheless, the arterial contractions elicited by depolarization or by α(1)-adrenoceptor stimulation decrease in aged, obese Zucker rats.

Changes in arterial blood pressure of a soluble cocoa fiber product in spontaneously hypertensive rats.

The effect produced by long-term intake of a soluble cocoa fiber product (SCFP) on the development of hypertension of spontaneously hypertensive rats (SHR) was evaluated. Twenty male 3-week-old SHR were divided into two groups of 10 animals that drank either tap water (control) or a solution of SCFP (0.75 g/day SCFP) until the 20th week of life. Five 20-week-old rats of each group were sacrificed. Tap water as drinking fluid was given to all the animals from the 20th to 24th week of life. The 24-week-old rats were also sacrificed. Body weight, liquid and dry food intake, and arterial blood pressure (tail cuff) were recorded weekly. Malondialdehyde (MDA), glucose and angiotensin converting enzyme (ACE) activity in the plasma from the sacrificed rats were also obtained, and we evaluated the relaxation caused by acetylcholine in the aorta from these animals. SCFP attenuated the development of hypertension in SHR; however, the withdrawal of SCFP caused an increase in blood pressure in the rats. Body weight gain was slower in the group treated with SCFP. SCFP increased liquid intake but decreased dry food intake in the rats. SCFP decreased plasma MDA concentrations and slightly decreased plasma ACE activity, but no differences were observed in plasma glucose and in the aorta responses to acetylcholine in both groups of 20-week-old SHR. We have demonstrated the antihypertensive and antioxidant properties of SCFP. The control of body weight and the control of increased angiotensin II may be involved in the antihypertensive effect of this product.

Péptidos antihipertensivos derivados de proteínas de leche y huevo / Peptides with antihypertensive activity obtained from milk and egg proteins

Algunos fragmentos de proteínas alimentarias, una vez liberados mediante hidrólisis, pueden producir un descenso del tono arterial. Son importantes los hidrolizados y péptidos provenientes de proteínas lácteas. Destacan los hidrolizados de caseína con tripsina, y los productos antihipertensivos obtenidos por fermentación de la leche con Lactobacillus helveticus. Estos productos contienen secuencias como Val-Pro-Pro (VPP) e Ile-Pro-Pro (IPP), que inhiben la enzima convertidor a de la angiotensina (ECA). Algunas cepas de Enterococcus faecalis también producen péptidos antihipertensivos inhibidores de la ECA. Entre estos péptidos destaca la secuencia LHLPLP. Existen asimismo péptidos e hidrolizados antihipertensivos derivados de proteínas de huevo. Podemos citar las secuencias FRADHPFL (ovokinina) y RADHPF (ovokinina 2-7) con actividad vasodilatadora endotelio-dependiente, y algunos hidrolizados de clara de huevo que inhibenla ECA. Los productos mencionados podrían utilizarse como ingredientes en alimentos funcionales. Algunos han probado ya su eficacia y seguridad en pacientes hipertensos

Antihypertensive hydrolysates and peptides have been isolated from food proteins. Among them, there are of particular interest the antihypertensive casein hydrolysates, and some antihypertensive products obtained when milk was fermented by Lactobacillus helveticus. The sequences Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), with angiotensin- converting enzyme (ACE) inhibitory activity, have been isolated from these fermented products. Selected Enterococcus faecalis strains can also produce milk derived peptides with ACE inhibitory and antihypertensive activities. The main of them is the sequence LHLPLP. Some studies also describe the production of antihypertensive hydrolysates and peptides from egg proteins. The sequences FRADHPFL (ovokinin) and RADHPFL (ovokinin 2-7),that have shown endothelium-dependent vasodilator activity, were obtained at first. Some egg white hydrolysates with ACE inhibitory activity have also been described. The idea of including the abovementioned products as functional food ingredients is particularly attractive. Some of them have already proved their safety and effectiveness in hypertensive patients

[Peptides with antihypertensive activity from milk and egg proteins]. / Péptidos antihipertensivos derivados de proteínas de leche y huevo.

Antihypertensive hydrolysates and peptides have been isolated from food proteins. Among them, there are of particular interest the antihypertensive casein hydrolysates, and some antihypertensive products obtained when milk was fermented by Lactobacillus helveticus. The sequences Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), with angiotensin-converting enzyme (ACE) inhibitory activity, have been isolated from these fermented products. Selected Enterococcus faecalis strains can also produce milk derived peptides with ACE inhibitory and antihypertensive activities. The main of them is the sequence LHLPLP. Some studies also describe the production of antihypertensive hydrolysates and peptides from egg proteins. The sequences FRADHPFL (ovokinin) and RADHPFL (ovokinin 2-7), that have shown endothelium-dependent vasodilator activity, were obtained at first. Some egg white hydrolysates with ACE inhibitory activity have also been described. The idea of including the above-mentioned products as functional food ingredients is particularly attractive. Some of them have already proved their safety and effectiveness in hypertensive patients.

Highly methoxylated pectin improves insulin resistance and other cardiometabolic risk factors in Zucker fatty rats.

In this study, we evaluated the effect of a highly methoxylated apple pectin (HMAP) on cardiometabolic risk factors in Zucker fatty rats. beta-Glucan, a fiber known for its hypocholesterolemic properties, also was used. The rats fed both fiber-enriched diets exhibited a reduction in body weight and in total cholesterol and triglycerides when compared to the Zucker fatty rats fed the standard diet. The effect on the lipid profile was more remarkable in the HMAP group. A decrease in blood glucose was only noticed in this group. Moreover, a decrease in plasma insulin, HOMA-IR, and HOMA-beta was noticed in the fiber groups, and in particular in the HMAP group, these variables being similar to the lean rats. Blood pressure and endothelial function were similar in all the Zucker fatty rats. These results warrant evaluation in humans to determine if HMAP could be used as a functional ingredient to reduce lipid profile, insulin resistance, and other cardiometabolic risk factors.

Determination of the antihypertensive peptide LHLPLP in fermented milk by high-performance liquid chromatography-mass spectrometry.

Among different lactic acid bacteria isolated from raw milk, 4 Enterococcus faecalis strains have stood out as producers of fermented milk with potent antihypertensive activity. The peptide beta-casein f(133-138), LHLPLP, was identified as one of the major peptides responsible for the activity of these fermented milk products. A simple method was developed to quantify this peptide in fermented milk using high-performance liquid chromatography coupled in line with mass spectrometry. This procedure does not require any previous sample fractionation or extraction, and direct analysis of the water-soluble extract obtained from the fermented milk can be performed. Validation studies showed sufficient specificity, reproducibility, linearity, and recovery, demonstrating that this method can be used for the routine quantification of LHLPLP during the production of fermented milk products. The developed method was readily applied to quantify the peptide LHLPLP under different fermentation conditions and with different aromatized products.

Efecto producido por la ingesta crónica de leche fermentada por Enterococcus faecalis CECT 5728 en ratas hipertensas / Effect produced by chronic intake of milk fermented by Enterococcus faecalis CECT 5728 in hypertensive rats

Introducción y objetivos. La fermentación de la leche por algunas bacterias genera péptidos con actividad inhibidora de la enzima convertidora de la angiotensina. Se evalúan los cambios de la presión arterial que produce en ratas espontáneamente hipertensas la administración crónica de leche fermentada por Enterococcus faecalis CECT 5728 con actividad inhibidora de esta enzima. Material y métodos. Se utilizaron ratas macho espontáneamente hipertensas recién destetadas con 3 semanas de vida. Las ratas se dividieron en cinco grupos que ingerían los siguientes productos líquidos: agua (control negativo), leche fermentada sin actividad inhibidora de la enzima convertidora de la angiotensina (testigo), captopril (100 mg/kg) (control positivo), leche fermentada por Enterococcus faecalis CECT 5728 y leche fermentada por Enterococcus faecalis CECT 5728 que estaba enriquecida en calcio. Los tratamientos se retiraron cuando las ratas tenían 20 semanas de vida. Se midió la presión arterial sistólica y diastólica de las ratas mediante el método del maguito en la cola cuando tenían 5, 10, 15, 20 y 25 semanas de vida. Resultados. El tratamiento con captopril disminuyó significativamente la presión arterial sistólica y diastólica de las ratas. La leche fermentada por Enterococcus faecalis CECT 5728 también disminuyó significativamente estas variables, pero su efecto fue menor que el de captopril. Los valores de la presión arterial sistólica y diastólica aumentaron tras la retirada de los tratamientos antihipertensivos. Conclusiones. Podría utilizarse la cepa bacteriana Enterococcus faecalis CECT 5728 para producir leches fermentadas útiles en el tratamiento y/o la prevención de la hipertensión

Introduction and objectives. Fermentation of milk by some bacteria generates peptides with angiotensin converting enzyme inhibitor activity. The changes of blood pressure that are produced in spontaneous hypertensive rats by the chronic administration of milk fermented by Enterococcus faecalis CECT 5728 with inhibitor activity of this enzyme are evaluated. Material and methods. Recently weaned spontaneous male hypertensive rats with 3 weeks of life were used. The rats were divided into five groups that took the following liquid products: water (negative control), fermented milk without angiotensin converting enzyme inhibitor activity (control), captopril (100 mg/kg) (positive control), milk fermented by Enterococcus faecalis CECT 5728, and milk fermented by Enterococcus faecalis CECT 5728 that was enriched in calcium. The treatments were withdrawn when the rats were 20 weeks old. Systolic and diastolic blood pressure of the rats was measured with the tail cuff method, when they were 5, 10, 15, 20 and 25 weeks old. Results. Treatment with captopril significantly decreased the systolic and diastolic blood pressure of the rats. Milk fermented by Enterococcus faecalis CECT 5728 also significantly decreased these variables, but its effect was less than that of captopril. The systolic and diastolic blood pressure values increased after withdrawal of the antihypertensive treatments. Conclusions. The bacterial strain Enterococcus faecalis CECT 5728 can be used to produce fermented milks useful in the treatment and/or prevention of hypertension

[Plasmapheresis: its use in multiple sclerosis and other demyelinating processes of the central nervous system. An observation study]. / Plasmaféresis: su utilidad en esclerosis múltiple y otros procesos desmielinizantes del sistema nervioso central. Estudio observacional.

INTRODUCTION: We present a retrospective observation study aimed at analyzing the value of plasmapheresis in the management of patients with multiple sclerosis (MS) and other acute demyelinating processes affecting the central nervous system (CNS) who show severe exacerbations that do not respond well to conventional therapy with corticoids. PATIENTS AND METHODS: A total of 11 patients were included in the study: nine with MS, one disseminated acute encephalomyelitis and one case of transverse myelitis. All of them presented an acute or subacute neurological deficit, which prevented them from carrying out their day to day activities, with or without repercussions on the EDSS, and with the risk of suffering a severe residual disability after not responding to intravenous methylprednisolone pulses. Each patient was submitted to three exchanges per week, for 2 weeks, with association of orally administered prednisone and they were then evaluated after the last session and at one, six and twelve months. RESULTS: Following plasmapheresis all the patients experienced a significant drop in disability and seven of them (77.7% of the total number with MS) even improved during the first month with respect to their basal situation ( an extension of the Lazarus effect ). After a year s follow up, 100% of the patients still maintained the basal situation that was recovered from before exacerbation, and only two relapses were recorded. The patients with MS presented a transient exacerbation after the second exchange. New therapy with immunosuppressants, immunomodulators or both was associated in eight cases. CONCLUSIONS: We consider plasmapheresis to be a safe, effective therapeutic procedure in the management of patients with MS and other demyelinating processes affecting the CNS. Its use should be considered as first choice in severe relapses and in swiftly progressing forms that do not respond to intravenous methylprednisolone.

Plasmaféresis: su utilidad en la esclerosis múltiple y otros procesos desmielinizantes del sistema nervioso central. Estudio observacional / Plasmaféresis: su utilidad en la esclerosis múltiple y otros procesos desmielinizantes del sistema nervioso central. Estudio observacional

Introducción. Presentamos un estudio observacional, retrospectivo, cuyo objetivo es analizar la utilidad de la plasmaféresis en el manejo de pacientes con esclerosis múltiple (EM) y otros procesos desmielinizantes agudos del sistema nervioso central (SNC) que presentan exacerbaciones graves rebeldes a la terapia convencional con corticoides. Pacientes y métodos. Incluimos 11 pacientes: nueve con EM, uno con encefalomielitis aguda diseminada y uno con mielitis transversa. Todos presentaban un déficit neurológico agudo o subagudo que les impedía la realización de sus actividades habituales, con o sin repercusión sobre la EDSS (escala ampliada del grado de discapacidad de Kurtzke), y con riesgo de sufrir discapacidad residual grave tras no responder a pulsos de metilprednisolona intravenosa. Cada paciente se sometió a tres recambios por semana, durante 2 semanas, con asociación de prednisona oral, y se evaluó tras la última sesión, al mes, a los seis y a los 12 meses. Resultados. Tras la plasmaféresis, todos experimentaron una reducción de la discapacidad significativa, y siete de ellos (77,7 por ciento del total con EM) incluso mejoraron respecto a su situación basal durante el primer mes (`ampliación del efecto Lázaro'). Tras un año de seguimiento, el 100 por ciento de los pacientes mantenía su recuperada situación basal anterior al empeoramiento, y se registraron únicamente dos brotes. Los pacientes con EM presentaron un `empeoramiento transitorio' tras el segundo recambio. Se asoció un nuevo tratamiento inmunosupresor, inmunomodulador, o ambos, en ocho casos. Conclusiones. Consideramos que la plasmaféresis es un procedimiento terapéutico eficaz y seguro en el manejo del paciente con EM y otros procesos desmielinizantes del SNC. Su utilización se debería considerar como de elección en los brotes graves y en formas con rápida progresión que no responden a la metilprednisolona intravenosa (AU)

Introduction. We present a retrospective observation study aimed at analyzing the value of plasmapheresis in the management of patients with multiple sclerosis (MS) and other acute demyelinating processes affecting the central nervous system (CNS) who show severe exacerbations that do not respond well to conventional therapy with corticoids. Patients and methods. A total of 11 patients were included in the study: nine with MS, one disseminated acute encephalomyelitis and one case of transverse myelitis. All of them presented an acute or subacute neurological deficit, which prevented them from carrying out their day-to-day activities, with or without repercussions on the EDSS, and with the risk of suffering a severe residual disability after not responding to intravenous methylprednisolone pulses. Each patient was submitted to three exchanges per week, for 2 weeks, with association of orally-administered prednisone and they were then evaluated after the last session and at one, six and twelve months. Results. Following plasmapheresis all the patients experienced a significant drop in disability and seven of them (77.7% of the total number with MS) even improved during the first month with respect to their basal situation (‘an extension of the Lazarus effect’). After a year’s follow-up, 100% of the patients still maintained the basal situation that was recovered from before exacerbation, and only two relapses were recorded. The patients with MS presented a ‘transient exacerbation’ after the second exchange. New therapy with immunosuppressants, immunomodulators or both was associated in eight cases. Conclusions. We consider plasmapheresis to be a safe, effective therapeutic procedure in the management of patients with MS and other demyelinating processes affecting the CNS. Its use should be considered as first choice in severe relapses and in swiftly progressing forms that do not respond to intravenous methylprednisolone (AU)

Alpha-vascular responses after short-term and long-term inhibition of nitric oxide synthesis.

Apart from the direct actions of nitric oxide (NO) on vascular smooth muscle, this factor may regulate cardiovascular functions through specific actions on alpha-adrenergic constrictor mechanisms. In this study we aim to establish whether the inhibition of the synthesis of this mediator could alter the vasoconstrictor responses mediated by alpha-adrenoceptor stimulation. We have been able to demonstrate that the blockage of the NO synthase really does exist, when both short- and long-term treatments with Nomega-nitro-Larginine methyl ester (L-NAME) are carried out. We have evaluated the concentration-dependent contractions induced by the selective alpha1-adrenoceptor agonists methoxamine and phenylephrine in isolated rat aorta rings in the following groups of animals: control, short-term L-NAME-treated (100 mg/kg i.p. 20 min before subjecting the animals to the experiments) and long-term L-NAME-treated (100 mg/kg per day in the drinking water for 7, 21, or 45 days). We have also evaluated the pressor responses to methoxamine and to the selective alpha-adrenoceptor agonist B-HT 920 using the pithed rat preparation in the same groups of animals. The contractile responses to methoxamine and phenylephrine were similar in the rat aorta preparations from control and short-term L-NAME-treated animals. On the contrary, in the rat aorta preparations from long-term L-NAME-treated animals these responses were clearly reduced when compared with the corresponding responses in those from control animals, the reduction being more marked when the treatment lasted longer. The pressor responses to methoxamine were also similar in control and short-term L-NAME-treated pithed rats. Nevertheless, the responses to B-HT 920 were greater in the latter. On the other hand, the dose-response curves to both alpha-adrenoceptor agonists were shifted to the right in a non-parallel manner in rats treated long term with L-NAME, the shift being, in the case of B-HT 920, more accentuated when the treatment lasted 21 or 45 days than when it lasted only 7 days. These results indicate that the short-term decrease in NO synthesis does not modify the vascular smooth muscle responses mediated by alpha1-adrenoceptor stimulation, but it does induce a potentiation of sympathetic vasoconstriction mediated by alpha2-adrenoceptors. Nevertheless, the long-term inhibition of NO synthesis causes a compensating decrease in the alpha1- and alpha2-vascular smooth muscle contractile responses.

Presence of a nitric oxide synthase inhibitor in the graft efflux during reperfusion in human liver transplantation.

Involvement of the nitric oxide (NO) system in complications following human orthotopic liver transplants (OLT) has been reported, but the contribution of the graft to the modulation of the NO system during reperfusion in normal OLT has not been characterized. We have studied the contribution of the graft efflux to the modulation of the NO system in 20 consecutive OLT. We evaluated its effects on isolated vascular reactivity of the rabbit and on rat cultured macrophages stimulated with lipopolysaccharide (LPS). In none of the donor liver biopsies was expression of inducible NO synthase (iNOS) activity by Northern or Western blot analysis found. Graft efflux after the onset of liver reperfusion, but not pre-transplant patient plasma, reversibly inhibited the acetylcholine-induced relaxation of norepinephrine-contracted rabbit aortic rings. Moreover, graft efflux reversibly inhibited NO production in rat macrophages treated with LPS, as evidenced by both a decrease in nitrite plus nitrate formation and a decrease in the production of [14C]citrulline from [14C]arginine. Addition of a 10% dilution of graft efflux to cultured rat macrophages incubated with LPS increased iNOS mRNA levels, suggesting direct inhibition of the enzyme but not of its expression. These results cannot be ascribed to the depletion of arginine the iNOS substrate since they can be reproduced even in the presence of an excess (10 mM) of exogenously added arginine. No correlation was found between the iNOS inhibitory activity in each sample and the corresponding clinical parameters related to either the graft function after the OLT or the existence of post-reperfusion syndrome. Our results indicate the existence of a soluble factor in the graft efflux from human OLT that reversibly and unspecifically inhibits NOS activity. Its involvement in the physiology and/or pathology of human liver diseases deserves further study.

The role of endothelium in the calcium-induced reduction of the contractile response of the rabbit aorta.

1. Increase of Ca2+ concentration in the bath solution diminishes the contractile response of isolated rabbit aorta rings to alpha 1-adrenoceptor agonists and KCl. 2. In intact preparations the contractions of methoxamine and phenylephrine were maximal when a 0.3- to 0.6-mM Ca2+ bath solution was used, and those of KCl were maximal with a 2.5-mM Ca2+ concentration. 3. The contractions of methoxamine and phenylephrine also were decreased by increasing the Ca2+ concentration above 1.25 mM in disrupted endothelium preparations and in those incubated in indomethacin (10(-5) M), N omega-nitro-L-arginine methyl ester (10(-4) M), or methylene blue (10(-6) M). 4. High organ bath Ca2+ concentrations also caused a decrease in KCl contractions using endothelium-denuded and the treated preparations, the responses being similar with 1.25 mM and 2.5-mM Ca2+ in the methylene blue-treated preparations, whereas they were greater with 1.25 mM Ca2+ in the others.

Further evidence for a peripheral sympathicolytic action of the antihypertensive cicletanine in rats.

The site and mechanism of action of the antihypertensive agent cicletanine have been studied. In the pithed rat model, intravenous (i.v.) cicletanine was able to reduce the elevated blood pressure induced by continuous infusion of the alpha 1-adrenergic agonist, methoxamine, in a dose-related manner. In strip preparation of the aorta from deoxycorticosterone (DOCA)-salt-treated rats, cicletanine was found to prevent the contraction induced by 1 microM noradrenaline. When subeffective doses of phentolamine (0.25 mg/kg p.o.) plus cicletanine (3 mg/kg p.o.) were given together, a clear-cut antihypertensive effect was observed in DOCA-salt rats. Moreover, subchronic administration of cicletanine (30 mg/kg p.o.), during the one month period of DOCA-salt administration to produce high blood pressure readings, was able to prevent cardiac noradrenaline depletion. These data suggest that the antihypertensive effect of cicletanine, which is clinically well tolerated, may be due to a multifactorial mechanism of its action, through which it might alter a number of physiological mediators while exercising a slight potency on each of them.