RESUMEN
Intrauterine growth restriction (IUGR) greatly increases perinatal mortality and morbidity rates, and leads to much greater risk for metabolic complications later in life. One such complication is the development of glucose intolerance or diabetes, which typically develops concurrently with abhorrent patterns of insulin secretions due to diminished ß-cell mass and impaired function as well as an overall reduction in pancreatic endocrine tissue. The mechanisms by which IUGR causes problems with health and function of the pancreatic islets are not well understood. Therefore, our goal for this study was to determine how materno-fetal inflammation (MI) affects ß-cell growth and function. To do this, we compared the average islet areas, plasma insulin concentrations, and blood glucose concentrations between MI-IUGR fetal lambs (n = 7) and control fetal lambs (n = 7). Pregnant ewes were injected with saline (controls) or 0.1-µg/kg bacterial lipopolysaccharide (LPS) every 3 d from days 100 to 115 of gestation (term = 150 d). Throughout late gestation, arterial blood of the fetus was periodically drawn and analyzed for plasma insulin (ELISA) and blood glucose (ABL90 FLEX) levels. On day 125 of gestation, ewes were euthanized and fetal pancreas was extracted. Sections of the fetal pancreas were then fixed in 4% paraformaldehyde, sectioned (cryostat) at a thickness of 8 µm, stained for insulin-positive area, and imaged on 20x magnification for analysis of average islet area. Between MI-IUGR and control fetuses, there were no differences in average islet areas (1675 ± 286 and 1678 ± 287 µm2, respectively), which indicates that MI did not impair growth and physical development of fetal islets. In addition, blood glucose was similar in all fetuses. However, results showed less (P ≤ 0.05) plasma insulin concentration in MI-IUGR fetuses (0.39 ± 0.07 ng/mL) than in controls (0.70 ± 0.09 ng/mL). This indicates impaired ß-cell functional capacity in MI-IUGR fetuses despite normal growth, which is quantified by a tendency (P = 0.08) for strong positive correlation (r = 0.91) between plasma insulin and islet area in control fetuses but an absence of correlation in MI-IUGR fetuses. From this study, we can conclude that MI-IUGR has no effect on the growth and physical development of ß cells; however, it does greatly affect their function.
RESUMEN
BACKGROUND & AIMS: Oxyntic atrophy is the hallmark of chronic gastritis. Many studies have sought to develop animal models for oxyntic atrophy, but none of them are reversible. We now report that rats administered high doses of DMP 777 demonstrate reversible oxyntic atrophy. METHODS: DMP 777 was administered to CD-1 rats by oral gavage (200 mg. kg(-1). day(-1)). Serum gastrin level, in vivo acid secretion, and gastric histological changes were evaluated in DMP 777-dosed animals. Direct effects of DMP 777 on parietal cells were evaluated by assessment of aminopyrine accumulation into isolated rabbit parietal cells, as well as by assessment of DMP 777 effects on acridine orange fluorescence and H(+),K(+)-adenosine triphosphatase (ATPase) activity in isolated tubulovesicles. RESULTS: Oral dosing with DMP 777 caused a rapid increase in serum gastrin levels and severe hypochlorhydria. DMP 777 inhibited aminopyrine accumulation into rabbit parietal cells stimulated with either histamine or forskolin. DMP 777 reversed a stimulated proton gradient in isolated parietal cell tubulovesicles. Oral dosing with DMP 777 led to rapid loss of parietal cells from the gastric mucosa. In response to the acute loss of parietal cells, there was an increase in the activity of the progenitor zone along with rapid expansion of the foveolar cell compartment. DMP 777 treatment also led to the emergence of bromodeoxyuridine-labeled cells and cells positive for periodic acid-Schiff in the basal region of fundic glands. With extended dosing over 3-6 months, foveolar hyperplasia and oxyntic atrophy were sustained while chief cell, enterochromaffin-like cell, and somatostatin cell populations were decreased. No histological evidence of neoplastic transformation was observed with dosing up to 6 months. Withdrawal of the drug after 3 or 6 months of dosing led to complete restitution of the normal mucosal lineages within 3 months. CONCLUSIONS: DMP 777 acts as a protonophore with specificity for parietal cell acid-secretory membranes. DMP 777 in high doses leads to the specific loss of parietal cells. Foveolar hyperplasia, loss of normal gland lineages, and the emergence of basal mucous cells appear as sequelae of the absence of parietal cells. The results suggest that parietal cells are critical for the maintenance of the normal mucosal lineage repertoire.
Asunto(s)
Gastritis/patología , Células Parietales Gástricas/patología , Estómago/patología , Estómago/fisiología , Naranja de Acridina , Aminopirina/farmacocinética , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Atrofia , Azetidinas , Radioisótopos de Carbono , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Colorantes Fluorescentes , Ácido Gástrico/metabolismo , Gastrinas/sangre , Gastritis/inducido químicamente , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Ionóforos/farmacología , Elastasa de Leucocito/antagonistas & inhibidores , Elastasa de Leucocito/metabolismo , Masculino , Necrosis , Nigericina/farmacología , Células Parietales Gástricas/enzimología , Células Parietales Gástricas/metabolismo , Piperazinas , Conejos , Ratas , Ratas Sprague-Dawley , RegeneraciónAsunto(s)
Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/toxicidad , Ciclosporina/farmacocinética , Ciclosporina/toxicidad , Inmunosupresores/farmacocinética , Inmunosupresores/toxicidad , Administración Oral , Animales , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Femenino , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Methyl-1-(butylcarbamoyl)-2-benzimidazole carbamate (benomyl) is a systemic fungicide which has been implicated in producing damage to the testes. The present investigation was undertaken to evaluate the functional and behavioral significance of this reported benomyl-induced damage to male rats using a 70-day feeding study followed by a 70-day recovery study. Adult male Wistar rats were fed laboratory chow containing 1.0, 6.3, or 203 ppm benomyl, with control animals receiving standard laboratory chow. Ejaculate sperm counts were significantly depressed (P less than or equal to 0.05) in male ingesting 203 ppm benomyl during the 70 day feeding phase. A significant decrease in relative testicular weights and a lowered male fertility index were observed in all benomyl-treatment groups. No significant alterations in plasma testosterone, LH, or FSH levels were observed during the feeding phase. Benomyl ingestion did not alter male copulatory behavior, nor was benomyl found to be an inducer of dominant lethal mutations. Identical studies performed during the recovery phase demonstrated that the benomyl-induced alterations in testicular function were reversible. The male fertility index, ejaculate sperm content, and testicular weights returned to control values during this phase.
Asunto(s)
Benomilo/toxicidad , Carbamatos/toxicidad , Reproducción/efectos de los fármacos , Animales , Copulación , Femenino , Feto/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ratas , Ratas Endogámicas , Espermatogénesis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Testículo/efectos de los fármacos , Testosterona/sangreRESUMEN
The purpose of this study was to determine whether repeated treatment (15 days) with d-amphetamine (AMP) or fenfluramine (FEN), administered after a daily 3 h feeding session (e.g. post-session), would result in tolerance or cross-tolerance to the decrement in food consumption induced by treatment with either drug before feeding (e.g. pre-session). Groups of males rats were treated IP with 0.5 ml saline, 1.0, 2.0, or 4.0 mg/kg AMP, or 2.5, 5.0, or 10.0 mg/kg FEN prior to a 3 h feeding session. For the next 15 sessions, the respective groups were treated post-session with saline (0.5 ml), AMP (4.0 mg/kg), or FEN (10 mg/kg). Following this 15 day post-session phase, each group again received this pre-session treatment. The initial pre-session treatment with all dosages of these two drugs produced a significant decrease in food consumption. Tolerance to the food intake suppressant effect of FEN, but not AMP, resulted from repeated post-session treatment with the same agent. Repeated post-session treatment with AMP resulted in a significant decrement in the suppressant activity of FEN on food intake, whereas the corresponding post-session treatments with FEN did not alter the pre-session effects of AMP except for an enhancement seen with higher AMP doses.
Asunto(s)
Dextroanfetamina/farmacología , Conducta Alimentaria/efectos de los fármacos , Fenfluramina/farmacología , Animales , Peso Corporal/efectos de los fármacos , Interacciones Farmacológicas , Tolerancia a Medicamentos , Masculino , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
The hepatic microsomal cytochromes P-450 and b5, as well as the enzymes of the hepatic microsomal electron-transport system (HMETS), including NADPH oxidase and NAPDH cytochrome c reductase, were monitored in male ICR mice (25 - 30 g) over a six-day period following repeated oral administration of methadone hydrochloride 12.5, 25, or 50 mg/kg per day, or an equivalent volume of water. Cytochrome P-450 content, when expressed per milligram of microsomal protein, was elevated as early as day 1 of administration. This increase in cytochrome P-450, which lasted throughout the period of administration, appeared to correlate with the previously reported increase in the hepatic microsomal enzyme methadone N-demethylase and tolerance to methadone lethality. The activities of the enzymes NADPH cytochrome c reductase and NADPH oxidase were both elevated significantly by day 2 of administration. However, these increases returned to control levels by day 6 of treatment. The only other cytochrome in the HMETS, cytochrome b5, showed no significant change following repeated oral methadone administration. Further, methadone administration depressed the hepatic microsomal protein content following two days of treatment and no elevation above control values was noted. The significance of these findings with respect to the role of the HMETS in the development of tolerance is discussed in some detail for methadone, as well as the findings previously reported by this laboratory for its acetylated congener, l-alpha-acetylmethadol.
Asunto(s)
Metadona/farmacología , Microsomas Hepáticos/enzimología , Administración Oral , Animales , Sistema Enzimático del Citocromo P-450/análisis , Tolerancia a Medicamentos , Transporte de Electrón/efectos de los fármacos , Dosificación Letal Mediana , Masculino , Metadona/administración & dosificación , Metadona/metabolismo , Ratones , NADH NADPH Oxidorreductasas/análisis , NADPH-Ferrihemoproteína Reductasa/análisis , Oxidorreductasas N-Desmetilantes/análisis , Proteínas/análisisRESUMEN
The microsomal cytochromes P-450 and b5 and the enzymes of the hepatic microsomal electron transport system (HMETS) including NADPH-cytochrome c reductase and NADPH oxidase activities were monitored in male ICR mice (25-30 g) over a six-day period following the repeated oral administration of 7, 14 and 28 mg/kg per day of l-alpha-acetylmethadol hydrochloride (LAAM) or an equivalent volume of water. Cytochrome P-450 and the microsomal enzyme activity of NADPH oxidase were maximally elevated (three- to four-fold above control values) by the third day of LAAM administration (28 mg/kg per day). These elevations not only correlated on a dose and a temporal basis with previously reported microsomal activities including LAAM N-demethylase, but also with the reported development of cellular tolerance and physical dependence following an identical regimen of LAAM. In addition, NADPH-cytochrome c reductase and cytochrome b5 increased in activity and content, respectively, after the repeated administration of this narcotic. However, the enzyme activity was first significantly elevated after only a single dose of LAAM. Thereafter, it showed a pattern of induction similar to that of NADPH oxidase. In contrast, cytochrome b5 was only elevated after the last repeated dose. The significance of these findings is discussed in some detail relative to the generation of the two analgesically active metabolites of LAAM.