(1/5009) Indirect evidence for cholinergic inhibition of intestinal bicarbonate absorption in humans.
BACKGROUND: The aim of the study was to test the hypothesis that in the fasting state, proximal intestinal HCO3- absorption, which depends on villus Na+/H+ exchanger activity, is tonically inhibited by a cholinergic atropine sensitive mechanism. SUBJECTS: The experiments were performed in 34 healthy volunteers and in eight patients with intestinal villus atrophy. METHODS: HCO3- absorption was measured with a modified triple lumen perfusion technique in the distal duodenum, the most proximal portion of the small intestine. The study was designed to compensate for the inhibitory effects of atropine on intestinal motor activity. RESULTS: Atropine had three effects on HCO3- transport: it reduced HCO3- concentration at the proximal aspiration site, it displaced the relation between HCO3- concentration and HCO3- absorption to the left, and it induced a significant acidification of the perfusate at the distal aspiration site. The magnitude of the stimulatory effect on HCO3- absorption was similar to the difference between patients with intestinal villus atrophy and healthy controls. CONCLUSION: The data suggest that, in the fasting state, duodenal HCO3- absorption, which depends on villus Na+/H+ exchanger activity, may be tonically inhibited by an atropine sensitive cholinergic mechanism. (+info)
(2/5009) Dietary control of triglyceride and phospholipid synthesis in rat liver slices.
1. The effect of dietary manipulation on the synthesis of triglycerides and phospholipids was investigated by determining the incorporation of labeled long-chain fatty acid or glycerol into these lipids in liver slices derived from normally fed, fasted, and fat-free refed rats. 2. Triglyceride synthesis was affected markedly by the dietary regime of the animal; the lowest rates were measured with fasted rats, and the highest ones with fat-free refed rats. 3. In contrast to triglyceride synthesis, phospholipid synthesis occured at virtually constant rates regardless of the dietary conditions. 4. Addition of large amounts of fatty acid to the incubation mixture resulted in a marked stimulation of triglyceride synthesis, whereas phospholipid synthesis was affected to a much smaller extent. 5. These results indicate that the synthesis of triglycerides and that of phospholipids are controlled independently, and that the availability of fatty acid in the cell contributes to the control of triglyceride synthesis. (+info)
(3/5009) Extremely low values of serum leptin in children with congenital generalized lipoatrophy.
Congenital generalized lipoatrophy (CGL) is a syndrome with multiple clinical manifestations and complete atrophy of adipose tissue. The exact mechanism of this disease remains unknown. One hypothesis presupposes an abnormal development of adipocytes. Leptin, the adipocyte-specific product of the ob gene, acts as a regulatory factor of body weight. In children, as in adults, leptin levels are correlated with body mass index (BMI) and body fat mass. Some authors have demonstrated that adults with congenital or acquired generalized lipoatrophy have decreased leptin concentrations. In order to study serum leptin profile during childhood in this disease, we measured serum leptin concentrations in six children aged 5.5-11 years suffering from CGL, and investigated the relationship between metabolic parameters and the variations in leptin levels. Serum leptin concentrations (1.19+/-0.32 ng/ml (+/- S.D.)) were extremely low compared with those observed in normal children. No significant correlation was found with BMI, which is known to be one of the major determinants of serum leptin. Serum leptin values were significantly correlated with fasting insulin levels (r=0.83, P=0.024). In conclusion, extremely low leptin values measured in children with CGL could be regarded as one among other diagnostic parameters. However, the detectable levels observed in all of these children support the evidence that a small amount of body fat is likely to be present in these patients, despite complete subcutaneous lipoatrophy. Our data suggest that this small amount of adipose tissue could be metabolically active and, at least in part, sensitive to insulin. Further investigations are required to uncover the pathophysiological mechanisms of this syndrome, known to be commonly associated with insulin resistance. (+info)
(4/5009) Induction of hepatic cytochromes P450 in dogs exposed to a chronic low dose of polychlorinated biphenyls.
Induction of cytochrome P450 isoforms, specifically CYP1A1, and their catalytic activities are potential biomarkers of environmental contamination by polychlorinated biphenyls (PCBs). In this study, dogs were exposed to 25 ppm or 5 ppm Aroclor 1248 (PCB mixture) daily in their diet for 10 or 20 weeks, respectively. Relative to controls, hepatic microsomes from dogs dosed with PCBs had higher levels of CYP1A1 detected in immunoblots and higher levels of EROD activity, but low levels of induction for CYP2B and PROD activity. Concentrations of 96 PCB congeners in serum and liver were evaluated using capillary chromatography. Results showed that all dogs exposed to PCB mixtures had higher levels of PCB in serum and liver. Dogs preferentially sequestered highly chlorinated PCB congeners in liver relative to serum. With these experiments, we demonstrated that EROD activity was a potentially sensitive marker of PCB exposure at 5 and 25 ppm. Furthermore, CYP1A1 and EROD activity were maximally induced in dogs consuming dietary concentrations only 2.5 times the maximal permissible level for human food (FDA). The value of CYP1A1 induction as a biomarker of PCB exposure was tenuous because neither CYP1A1 levels nor EROD activity correlated with total PCB body burden. However, a small subset of congeners were identified in liver that may strongly influence EROD and PROD induction. Finally, two dogs in the 25 ppm dose group were fasted for 48 h. After 24 h of fasting, several new congeners appeared in the serum and remained in the serum for the remainder of the fast. The fast caused a 293% increase in PCB concentration in serum. This increase has strong implications regarding mobilization of toxic PCBs in wildlife during fasting (e.g., migration, hibernation). (+info)
(5/5009) Effect of fasting on temporal variation in the nephrotoxicity of amphotericin B in rats.
Evidence for temporal variation in the nephrotoxicity of amphotericin B was recently reported in experimental animals. The role of food in these variations was determined by studying the effect of a short fasting period on the temporal variation in the renal toxicity of amphotericin B. Twenty-eight normally fed and 28 fasted female Sprague-Dawley rats were used. Food was available ad libitum to the fed rats, while the fasted animals were fasted 12 h before and 24 h after amphotericin B injection to minimize stress for the animals. Water was available ad libitum to both groups of rats, which were maintained on a 14-h light, 10-h dark regimen (light on at 0600 h). Renal toxicity was determined by comparing the levels of excretion of renal enzyme and the serum creatinine and blood urea nitrogen (BUN) levels at the time of the maximal (0700 h) or the minimal (1900 h) nephrotoxicity after the intraperitoneal administration of a single dose of dextrose (5%; control group) or amphotericin B (50 mg/kg of body weight; treated group) to the rats. The nephrotoxicities obtained after amphotericin B administration at both times of day were compared to the nephrotoxicities observed for time-matched controls. In fed animals, the 24-h urinary excretion of N-acetyl-beta-D-glucosaminidase and beta-galactosidase was significantly higher when amphotericin B was injected at 0700 and 1900 h. The excretion of these two enzymes was reduced significantly (P < 0.05) in fasting rats, and this effect was larger at 0700 h (P < 0.05) than at 1900 h. The serum creatinine level was also significantly higher (P < 0.05) in fed animals treated at 0700 h than in fed animals treated at 1900 h. Fasting reduced significantly (P < 0.05) the increase in the serum creatinine level, and this effect was larger in the animals treated at 0700 h. Similar data were obtained for BUN levels. Amphotericin B accumulation was significantly higher (P < 0.05) in the renal cortexes of fed rats than in those of fasted animals, but there was no difference according to the time of injection. These results demonstrated that fasting reduces the nephrotoxicity of amphotericin B and that food availability is of crucial importance in the temporal variation in the renal toxicity of amphotericin B in rats. (+info)
(6/5009) Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids.
Ethambutol (EMB) is the most frequent "fourth drug" used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (+/- standard deviation) EMB maximum concentration of drug in serum (Cmax) of 4.5 +/- 1.0 micrograms/ml, time to maximum concentration of drug in serum (Tmax) of 2.5 +/- 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) of 28.9 +/- 4.7 micrograms.h/ml. In the presence of antacids, subjects had a mean Cmax of 3.3 +/- 0.5 micrograms/ml, Tmax of 2.9 +/- 1.2 h, and AUC0-infinity of 27.5 +/- 5.9 micrograms.h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean Cmax of 3.8 +/- 0.8 micrograms/ml, Tmax of 3.2 +/- 1.3 h, and AUC0-infinity of 29.6 +/- 4.7 micrograms.h/ml. These reductions in Cmax, delays in Tmax, and modest reductions in AUC0-infinity can be avoided by giving EMB on an empty stomach whenever possible. (+info)
(7/5009) Alloxan in vivo does not only exert deleterious effects on pancreatic B cells.
The aim of the experiment was to investigate the mechanism of harmful alloxan action in vivo. 75 mg/kg b.w. of this diabetogenic agent were administered to fasting rats. Two minutes later the animals were decapitated. It was observed that alloxan caused a distinct rise in blood insulin and glucose levels with a concomitant drop of free fatty acids. The amount of sulfhydryl groups in the liver of alloxan-treated rats was decreased and glutathione peroxidase activity was substantially higher. These results indicate that some changes observed in alloxan-induced diabetes can not only be the consequence of B cells damage by alloxan but may also be the result of its direct influence on other tissues. It was also observed that glucose given 20 min before alloxan injection only partially protected against the deleterious effects of alloxan. (+info)
(8/5009) Lipoprotein lipase expression level influences tissue clearance of chylomicron retinyl ester.
Approximately 25% of postprandial retinoid is cleared from the circulation by extrahepatic tissues. Little is known about physiologic factors important to this uptake. We hypothesized that lipoprotein lipase (LpL) contributes to extrahepatic clearance of chylomicron vitamin A. To investigate this, [3H]retinyl ester-containing rat mesenteric chylomicrons were injected intravenously into induced mutant mice and nutritionally manipulated rats. The tissue sites of uptake of 3H label by wild type mice and LpL-null mice overexpressing human LpL in muscle indicate that LpL expression does influence accumulation of chylomicron retinoid. Skeletal muscle from mice overexpressing human LpL accumulated 1.7- to 2.4-fold more 3H label than wild type. Moreover, heart tissue from mice overexpresssing human LpL, but lacking mouse LpL, accumulated less than half of the 3H-label taken up by wild type heart. Fasting and heparin injection, two factors that increase LpL activity in skeletal muscle, increased uptake of chylomicron [3H] retinoid by rat skeletal muscle. Using [3H]retinyl palmitate and its non-hydrolyzable analog retinyl [14C]hexadecyl ether incorporated into Intralipid emulsions, the importance of retinyl ester hydrolysis in this process was assessed. We observed that 3H label was taken up to a greater extent than 14C label by rat skeletal muscle, suggesting that retinoid uptake requires hydrolysis. In summary, for each of our experiments, the level of lipoprotein lipase expression in skeletal muscle, heart, and/or adipose tissue influenced the amount of [3H]retinoid taken up from chylomicrons and/or their remnants. (+info)