Effects of nitric oxide inhibitors in mice with bladder outlet obstruction

ABSTRACT Purpose To investigate the lower urinary tract changes in mice treated with L-NAME, a non-selective competitive inhibitor of nitric oxide synthase (NOS), or aminoguanidine, a competitive inhibitor of inducible nitric oxide synthase (iNOS), after 5 weeks of partial bladder outlet obstruction (BOO), in order to evaluate the role of constitutive and non-constitutive NOS in the pathogenesis of this experimental condition. Materials and Methods C57BL6 male mice were partially obstructed and randomly allocated into 6 groups: Sham, Sham + L-NAME, Sham + aminoguanidine, BOO, BOO + L-NAME and BOO + aminoguanidine. After 5 weeks, bladder weight was obtained and cystometry and tissue bath contractile studies were performed. Results BOO animals showed increase of non-voiding contractions (NVC) and bladder capacity, and also less contractile response to Carbachol and Electric Field Stimulation. Inhibition of NOS isoforms improved bladder capacity and compliance in BOO animals. L-NAME caused more NVC, prevented bladder weight gain and leaded to augmented contractile responses at muscarinic and electric stimulation. Aminoguanidine diminished NVC, but did not avoid bladder weight gain in BOO animals and did not improve contractile responses. Conclusion It can be hypothesized that chronic inhibition of three NOS isoforms in BOO animals leaded to worsening of bladder function, while selective inhibition of iNOS did not improve responses, what suggests that, in BOO animals, alterations are related to constitutive NOS.

possible protective role of aminoguanidine in gentamicin-induced ototoxicity in guinea pig: a histological and immunohistochemical study

Introduction: Gentamicin is an ototoxic drug affecting both auditory and vestibular cells. Reactive oxygen species might play important role in the molecular pathway of this ototoxicity. Aminoguanidine is one of the guanidine derivatives and is considered as an antioxidant therapy

Aim of the work: to investigate the possible protective effect of aminoguanidine on ototoxicity induced by gentamicin in guinea pig

Materials and methods: Twenty one adult male guinea pigs were used. They were divided into three groups, seven animals each. Group I: served as a control group. Group II: I.M. injection of gentamicin [80 mg/kg/day] was used for 14 days. Group III: animals received gentamicin in the same way as group II and then followed by aminoguanidine [100 mg/kg/ day] administration using a gastric tube for 14 days. At the end of experiment, the cochlea was excised and prepared for light [LM] and scanning electron microscope [SME] examination. Immunohistochemichal technique was done to detect iNOS. Morphometric and statistical studies were also done

Results: By LM and SME examination, the present study showed that aminoguanidine protected the structure of organ of Corti in the cochlea by decreasing the degeneration of hair cells and other supporting cells. It also showed a significant decrease in the iNOS immune-reactivity in organ of Corti, stria vascularis and bipolar cells in spiral ganglia compared to group II

Conclusion: Aminoguanidine is a promising and successful antioxidant therapy for ototoxicity

Could Nafamostat or Gabexate Prevent the Post Endoscopic Retrograde Cholangiopancreatography Pancreatitis? / 대한소화기학회지

BACKGROUND/AIMS: ERCP is the most common procedure for the diagnosis and treatment of bile duct and pancreatic disease, but Post-ERCP pancreatitis makes poor outcome in some cases. The protease inhibitors, nafamostat and gabexate, have been used to prevent pancreatitis related to ERCP, but there is some debate. We tried to evaluate the efficacy of gabexate and nafamostat for the prevention of post-ERCP pancreatitis. METHODS: Two hundred forty two patients (73 patients in the gabexate group, 88 patients in the nafamostat group and 81 patients in the placebo group) were included in the study after selective exclusion. The incidence of pancreatitis after ERCP was compared among groups. RESULTS: The incidence of pancreatitis were 6.8% in the gabexate group, 5.7% in the nafamostat group and 6.2% in the placebo group (p=0.954). CONCLUSIONS: There was no meaningful difference among the gabexate, nafamostat and placebo group.

Involvement of nitric oxide pathways in neurogenic pulmonary edema induced by vagotomy

OBJECTIVE: The objective of this study was to evaluate the involvement of peripheral nitric oxide (NO) in vagotomy-induced pulmonary edema by verifying whether the nitric oxide synthases (NOS), constitutive (cNOS) and inducible (iNOS), participate in this mechanism. INTRODUCTION: It has been proposed that vagotomy induces neurogenic pulmonary edema or intensifies the edema of other etiologies. METHODS: Control and vagotomized rats were pretreated with 0.3 mg/kg, 3.0 mg/kg or 39.0 mg/kg of L-NAME, or with 5.0 mg/kg, 10.0 mg/kg or 20.0 mg/kg of aminoguanidine. All animals were observed for 120 minutes. After the animals' death, the trachea was catheterized in order to observe tracheal fluid and to classify the severity of pulmonary edema. The lungs were removed and weighed to evaluate pulmonary weight gain and edema index. RESULTS: Vagotomy promoted pulmonary edema as edema was significantly higher than in the control. This effect was modified by treatment with L-NAME. The highest dose, 39.0 mg/kg, reduced the edema and prolonged the survival of the animals, while at the lowest dose, 0.3 mg/kg, the edema and reduced survival rates were maintained. Aminoguanidine, regardless of the dose inhibited the development of the edema. Its effect was similar to that observed when the highest dose of L-NAME was administered. It may be that the non-selective blockade of cNOS by the highest dose of L-NAME also inhibited the iNOS pathway. CONCLUSION: Our data suggest that iNOS could be directly involved in pulmonary edema induced by vagotomy and cNOS appears to participate as a protector mechanism.

Antagonic effect of the inhibition of inducible nitric oxide on the mortality of mice acutely infected with Escherichia coli and Bacteroides fragilis

Sepsis, the leading cause of death in intensive care units, is associated with overproduction of nitric oxide (NO) due to inducible NO synthase (iNOS), responsible for some of the pathologic changes. Aminoguanidine (AG) is a selective iNOS inhibitor with reported inconsistent actions in sepsis. To investigate the influence of iNOS, we studied models of acute bacterial sepsis using acute challenges with aerobic (Escherichia coli) and anaerobic (Bacteroides fragilis) bacteria in the presence of AG. Six-week-old, 23 g, male and female BALB/c and C57Bl/6j mice, in equal proportions, were inoculated (ip) with bacteria in groups of 4 animals for each dose and each experiment in the absence or presence of AG (50 mg/kg, ip, starting 24 h before challenge and daily until day 6) and serum nitrate was measured by chemiluminescence. Both types of bacteria were lethal to mice, with an LD50 of 6 nephelometric units (U) for E. coli and 8 U for B. fragilis. Nitrate production peaked on the second day after E. coli inoculation with 8 and 6 U (P < 0.05), but was absent after non-lethal lower doses. After challenge with B. fragilis this early peak occurred at all tested doses after 24 h, including non-lethal ones (P < 0.05). AG-treated mice challenged with E. coli presented higher survival (P < 0.05) and increased LD50. AG-treated mice challenged with B. fragilis had lower LD50 and higher mortality. Control AG-treated animals presented no toxic effects. The opposite effect of iNOS blockade by AG in these models could be explained by restriction of oxygen for immune cells or an efficient action of NO in anaerobic localized infections. The antagonic role of NO production observed in our bacterial models could explain the reported discrepancy of NO action in sepsis.

Analisis ecocardiografico del efecto de diferentes inhibidores del intercambiador Na+/H+ sobre la estructura y funcion sistolica del ventriculo izquierdo en ratas espontaneamente hipertensas / Echocardiographic analysis of the effect of different Na+/H+ exchanger inhibitors on left

El presente estudio fue proyectado para analizar mediante ecocardiograma los efectos del HOE 642 (cariporide) (HOE) y del BIIB 723 (BIIB) sobre la estructura y función sistólica del ventrículo izquierdo en ratas espontáneamente hipertensas (SHR)- 8 con 30 mg/kg/día de HOE, 8 con 30 mg/kg/día de BIIB durante 30 días y 4 sin tratamiento (grupo control) durante esos 30 días. Los distintos parámetros analizados no mostraron cambios durante ese período en las ratas controles. Si bien el HOE determinó un leve descenso de la presión arterial (C: 184 ± 1.75 mm Hg; 30d:176.20 ± 2.60 mm Hg, p <0.01), no detectada con BIIB,ambas drogas provocaron un aumento del estrés sistólico pico (HOE C:166 ± 29 kdinas/cm2; 30d: 204 ± 34kdinas/cm2, p <0.04. BIIB C: 164 ± 25.90 kdinas/cm2; 30d: 234 ± 29.30 kdinas/cm2, p<0.02).Tanto HOE comoBIIB redujeron significativamente la masa ventricular izquierda (MVI) (HOE C: 612.50±50 mg; 30d:452 ± 37 mg,p <0.01; BIIB C: 544 ± 16mg; 30 d: 374 ± 25 mg, p<0.01). El porcentaje de acortamiento endocárdico no semodificó luego del tratamiento con HOE (C: 62.30 ± 2.75; 30d 65.50 ± 2.40%, ns) y BIIB (C: 63.20 ± 2.39%;30d 67.20 ± 1.62%, ns). Los resultados analizados permiten concluir que ambos inhibidores determinaron similarreducción de la MVI. Esa reducción se acompañó de mejoría en los índices de evaluación de la función sistólica ventricular izquierda, pese al incremento del estrés sistólico pico. Estas evidencias sugieren que independientemente del inhibidor utilizado se encuentra un aumento del inotropismo, previamente comprometidodurante el desarrollo de la hipertrofia

The aim of this study was to analyze by echocardiogram, the action of two Na+/H+ exchange, inhibitors, HOE 642 (HOE) and BIIB 723 (BIIB) on left ventricular (LV) mass and LV systolic function. We studied 16 spontaneously hypertensive rats (SHR), 8 treated with HOE 30 mg/kg/day, 8 with 30 mg/kg/day of BIIB during 30 days and 4 SHR as controls during those 30 days. Results are expressed as mean values ± SEM. The systolic blood pressure and theechocardiograpic parameters examined did not evidence changes during that period in the controls rats. Eventhough HOE determined a slight decrease in blood pressure (HOE C: 184 ± 1.75 mm Hg; HOE 30d: 176.20 ±2.60 mm Hg - p <0.01) which was not detected with BIIB, both drugs provoked an increase of peak systolic stress (HOE C: 166 ± 29 kdynes/cm2; HOE 30d: 204 ± 34 kdynes/cm2, p <0.04; BIIB C: 164 ± 25.90 kdynes/cm2; BIIB 30d: 234 ± 29.30 kdynes/cm2, p <0.02). HOE and BIIB reduced LV mass after 30 days of administration (HOE C: 612.50 ± 50 mg; 30d: 452 ± 37 mg, p <0.01. BIIB C: 544 ± 16mg; 30d: 374 ± 25 mg, p <0.01). LV endocardial shortening was similar independently of the NHE inhibitors used (HOE C: 62.30 ± 2.75%; 30d: 65.50 ± 2.40%, ns. BIIB C: 63.20 ± 2,39%; 30d 67,20 ± 1.62%, ns). These data demonstrate that long-treatment with HOE or BIIB produced similar LV mass regression without changes in endocardial fractional shortening in spite of the increase of peak systolic stress. This finding could represent an increased inotropism previously depressed by the development of hypertrophy

Neuroprotective agents in acute ischemic stroke.

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. A wide variety of drugs have been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They included calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilazad and ebselen, enlimomab, GABA agonist clomethiazole, the sodium channel antagonist fosphenytoin, magnesium, glycine site antagonist GV150526 and piracetam. Furthermore, the mechanisms that underlie the development of focal ischemic injury continue to be discovered, opening new therapeutic perspective for neuroprotection that might clinically be applicable in the future.

Tratamiento de la neuropatía diabética / Diabetic neuropathic treatment

La polineuropatía diabética es una complicación progresiva que afecta a la mayoría de los pacientes con diabetes mellitus de larga duración, y que es capaz de deteriorar gravemente su calidad de vida. En los últimos años se han desarrollado medidas terapéuticas que permiten mejorar los síntomas y la función nerviosa, y en algunos casos, prevenir y detener el daño neuronal, e incluso, favorecer la regeneración de las fibras nerviosas. La utilidad de estos tratamientos se apoya en investigaciones realizadas en animales y en seres humanos como son: a) control estricto de la glucemia (insulina), b) inhibición de la aldosa reductasa (tolrestato), c) prevención de la glucación de proteínas canino-guanidina), d) disminución de la isquemia nerviosa (vasodilatadores, ácido gamalinolénico), y e) administración de factores neurotróficos (gangliosidos). El más investigado y con evidencias más sólidas de su utilidad es el control de la glucemia. Se sugiere que el tratamiento se inicie tempranamente, pues en la neuropatía avanzada hay una severa pérdida de fibras nerviosas que dificulta la recuperación

Glicosilación no enzimática de proteínas: su rol en las complicaciones crónicas de la diabetes y el envejecimiento / No-enzymatic glycosylation of proteins: role in aging and in the chronic complications of diabetes

En los últimos 15 años la glicosilación no enzimática de las proteínas ha pasado de ser un fenómeno de importancia bromatológica, a tener relevancia en procesos tales como el envejecimiento y las complicaciones crónicas que desarrollan los pacientes diabéticos. El enfoque inicial se centró en los productos de glicosilación temprana de proteínas o productos de Amadori; más recientemente se ha resaltado la formación de los productos de glicosilación avanzada de proteínas como uno de los factores causales de las alteraciones diabéticas y la senilidad. Se han diseñado fármacos que interfieren con las vías de formación de estos productos de glicosilación no enzimática, los cuales tendrían un importante potencial terapéutico en el control de la aparición de las complicaciones crónicas en la diabetes. La determinación en el laboratorio de los productos de glicosilación de proteínas es una herramienta muy útil para el pronóstico de la calidad de vida de un individuo, ya sea normal o diabético, y para el seguimiento del control metabólico a mediano y largo plazo en los pacientes diabéticos

Terapeutica antihipertensiva con guanfacina: informe clínico de un estudio multicentrico nacional en 2540 pacientes / Antihypertensive therapeutics with guanfacine: clinical report of a multicenter nationwide open study in 2540 patients

Este estudio multicéntrico nacional desarrollado en 1983, pudo concretarse gracias a la colaboración de 800 médicos clínicos, que residen en toda la extensión territorial del país. La coordinación y las conclusiones sobre los datos obtenidos estuvieron a cargo del Profesor Adjunto Dr. Carlos A. Feldstein (U.B.A.). El análisis estadístico de toda la información acumulada fue realizado por el Dr. Ricardo Glancszpigel. El Servicio de Investigaciones Clínicas de Sandoz Argentina S.A.I.C. expresa su agredecimiento a todos los colegas que prestaron su experiencia en este estudio

Tratamiento a corto plazo de la hipertensión arterial esencial con una droga bloqueadora posganglionar de acción rápida (bethanidine) / Short-term treatment of essential arterial hypertension with a rapid release postganglial blocking drug (bethanidine)

Se estudió el efecto hipotensor de una droga de acción bloqueadora adrenérgica neuronal (bethanidine) en asociación con propranolol y furosemida; estas últimas a dosis fijas pre y durante la instauración del tratamientos, en 14 pacientes hipertensos esenciales (HTAE) severos, alguno de los cuales tenía insuficiencia renal crónica, ligera y moderada. El período de estudio fue de 3 meses con dosis de bethanidine entre 20 y 80mg/d (promedios de 40,0 + ou - 14,14 a 54,28 + ou - 18 mg/d). Se controló por completo la presión arterial en el 85,7% (12/14) de los pacientes y en los restantes 14,3% se obtuvo un control parcial. La hipotensión postural, aunque frecuente, fue bien tolerada y desapareció rápidamente con reducción de la dosis. Se plantea que la asociación de bethanidine con propranolol y furosemida es adecuada para el tratamientos de la HTAE severa, de difícil control con los tratamientos clásicos

Avaliaçäo of guanfacina na hipertensäo arterial moderada e grave / Evaluation of guanfacine in the treatment of moderate and severe arterial hypertension

Estudaram os autores o efeito da guanfacina em 21 pacientes portadores de hipertensäo arterial moderada (15 pacientes) e grave (6 pacientes), fazendo uma extensa revisäo da literatura. A avaliaçäo, em ensaio näo comparativo, foi feita a curto e a médio prazos, compreendendo um período inicial de quatro semanas e os seguintes em três meses. As doses variaram de 1 a 3mg/dia em uma única tomada. Durante a avaliaçäo a médio prazo associou-se a furosemide na dose de 40 a 80mg. Durante a avaliaçäo a curto prazo, cinco pacientes hipertensos moderados normalizaram a pressäo arterial e os demais (16 pacientes) obtiveram reduçäo dos níveis tensionais. Nos seis pacientes avaliados por quatro meses, os níveis pressóricos médios praticamente normalizaram na posiçäo de pé (145,0 x 96,7mmHg) ao final do ensaio, permanecendo um pouco acima do normal nas posiçöes deitada e após caminhada (166,3 x 102,5mmHg)