Evaluation of jojoba oil as a low-energy fat. 1. A 4-week feeding study in rats

The nutritional properties of jojoba oil (JO) were examined in a 4-wk feeding study of rats fed a diet with JO at dose levels of 2.2, 4.5 and 9%, supplemented with a conventional fat up to 18%. General health, survival and food intake were not adversely affected. Body-weight gains showed a dose-related decline, which amounted to 20% of the body weight in the high-dose group of both sexes. Clinical chemistry revealed significantly increased levels of various enzymes that were indicative of cell damage. Haematology showed a dose-related increase in white blood cells. On necropsy an apparent distension of the small intestine was found. Histopathological evaluation revealed marked intestinal changes characterized by massive vacuolization and lipid deposition in the enterocytes, accompanied by distension of the villi and an increased cell turnover of small intestinal cells. Faeces production and faeces lipid content were increased with increasing JO levels. The recovery of JO in the faeces also increased in a dose-related manner and was found to be correlated with the intestinal histopathological changes. The significant adverse clinical and histopathological effects observed in this study imply that JO cannot be considered as a promising alternative dietary fat with a low digestibility.     

Toxicological evaluation of sicklepod and black nightshade seeds in short-term feeding studies in rats

Nutritionally complete diets containing sicklepod or black nightshade seed at 1, 2, 4, 8, 16 and 32% were fed to groups of three to five male Sprague-Dawley rats in a series of short-term (8-9 days) toxicity studies. Gross clinical observations, body weights and feed and water intake data were recorded. Clinical chemistry analyses, haematology, histology and bone-marrow evaluation for evidence of clastogenic effects were performed. In addition, groups of five female rats were fed sicklepod seed at the same dosages to compare effects on body weight and feed and water consumption. For sicklepod, all of the animals fed diet containing 32% seed and one (female) fed diet containing 16% seed died by day 8. Body-weight gain and feed and water consumption were decreased with increasing doses of sicklepod seed. Other effects of sicklepod seed included: testicular hypospermia at dosages of 8% or greater, and bone-marrow depletion, reduced numbers of polychromatic erythrocytes in the bone marrow, increased neutrophil:lymphocyte ratio, and red nasal discharge at 16%. Black nightshade seed was relatively non-toxic compared with the sicklepod. The principal adverse effects of black nightshade were decreased body-weight gain and feed consumption, which occurred during the first 3 days of the study in animals fed 32% seed.     

Effect of metoclopramide, bethanechol, and loperamide on gastric residence time, gastric emptying, and mouth-to-cecum transit time

The effects of metoclopramide, bethanechol, and loperamide on the gastric residence time (GRT), gastric emptying (GE), and mouth-to-cecum transit time (MCTT) of a solution were investigated in three separate studies of five healthy male volunteers each. Metoclopramide in doses of 5, 10, and 15 mg prolonged GRT by 33, 88, and 162%, respectively, almost reaching statistical significance (p 0.058). A relationship was observed between GRT prolongation, and metoclopramide area under the plasma-time curve (p 0.01) and metoclopramide observed time to maximum concentration (p 0.01). Metoclopramide had an inconsistent effect on MCTT. Bethanechol 50 mg prolonged GRT by 64% (p 0.031) and had no effect on MCTT. Loperamide at doses of 2 and 8 mg prolonged GRT by 18 and 115% (p 0.043) and MCTT by 30 and 130% (p 0.0001), respectively. None of these motility-altering agents affected GE.     

Effect of peppermint oil and caraway oil on gastrointestinal motility in healthy volunteers: a pharmacodynamic study using simultaneous determination of gastric and gall-bladder emptying and orocaecal transit time

BACKGROUND: Although peppermint oil and caraway oil are frequently used in herbal drugs for abdominal discomfort and pain, the pharmacological insights into their effects on the gastrointestinal tract are poor. METHODS: The pharmacodynamic effects of 90 mg peppermint oil (WS 1340) and 50 mg caraway oil (WS 1520) on the motility of the stomach and gall-bladder, and on the orocaecal transit time, in comparison with placebo, 10 mg cisapride and 10 mg n-butylscopolamine, were studied in 12 healthy volunteers. The study involved simultaneous ultrasonic determination of gastric and gall-bladder emptying, together with assessment of the orocaecal transit time using the lactulose H2 breath test. The combination of these methods allows three gastrointestinal organs to be studied in one subject simultaneously. RESULTS: The antral filling time was comparable with placebo, peppermint oil, caraway oil and cisapride, whereas it was significantly shortened (P = 0.04, two-sided paired t-test) with n-butylscopolamine. The gastric emptying time did not differ significantly between placebo, peppermint oil, caraway oil and cisapride, but was significantly prolonged by n-butylscopolamine (P = 0.04, two-sided paired t-test). Complete inhibition of gall-bladder emptying was caused by both oils and n-butylscopolamine. Cisapride significantly shortened gall-bladder emptying compared with placebo (P = 0.02, two-sided signed rank test). The orocaecal transit time was significantly prolonged by peppermint oil (P = 0.004) and n-butylscopolamine (P = 0.002), but not significantly prolonged by caraway oil (P = 0.06); it was significantly shortened by cisapride (P = 0.04, all two-sided paired t-test). CONCLUSIONS: Peppermint oil and caraway oil show a relaxing effect on the gall-bladder and the former slows small intestinal transit. Further studies should investigate the effects of both oils on a maximal contraction stimulus on the gall-bladder, and in patients suffering from motility disorders.     

Comparison of cereal-based diet with purified diet by short-term feeding studies in rats, mice and hamsters, with emphasis on toxicity characteristics.

Animal diets used in toxicity studies are prepared either from natural ingredients (cereal-based diet) or from more refined products (purified diet). The type of diet may influence both the outcome of the study and the values obtained with the various parameters in test and control animals. To detect the parameters sensitive to changes in diet composition, short-term (4-wk) studies were conducted in rats, mice and hamsters fed either a cereal-based diet or the AIN-76A purified diet supplemented with vitamins and minerals at the highest recommended levels for each of the species used. Although the purified diet was more palatable to rats and showed a higher protein quality, growth rate and food intake were generally slightly higher with the cereal-based diet in each of the species examined. The haematological values of the two diet groups were generally comparable. On the cereal-based diet the production of faeces was considerably higher than on the purified diet and was accompanied by a higher weight of the caecum. These findings were attributed to the relatively high level and mixed composition of the fibre fraction in the cereal-based diet. Blood levels of cholesterol and phospholipids were clearly lower on the cereal-based diet than on the purified diet. Because the differences were probably due to the level and composition of the fibre fraction, they support the suggestion to replace the 5% cellulose of the AIN-76A diet by a higher level of a more composite but well defined source of dietary fibre.     

Effects of gravity on gastric emptying, intestinal transit, and drug absorption.

The effects of microgravity on the physiologic response of the human body, the physical properties of gastrointestinal contents, and the influence these responses have on drug absorption are becoming more and more critical as the duration of humans in the hostile space environment dramatically increases. In this environment, some conventional oral dosage forms may be severely limited as an effective drug regimen. To understand the effects of microgravity, one must first understand the basic forces acting on a particle moving through a walled-tube such as the small intestine: gravity (FG), buoyancy (FB), and drag (FD). These forces can be combined and rearranged into a dimensionless ratio of gravitational forces to viscous forces. This is the most important dimensionless group influencing the motion of a particle relative to the fluid. Gastric emptying is highly influenced by several factors: volume, calories, exercise, size, density, temperature, viscosity, osmolality as well as those factors associated with physiologic responses: splanchnic blood flow, body position, and electrolyte balance. This array of factors can lead to variability in drug plasma levels. In the absence of gravity, the factors of size and density would appear to be most directly altered due to their dependence on the force of gravity. Intestinal transit rate in a gravity environment is highly dependent on the motility state of the GI tract either fasted or fed partly due to the higher viscosities of chyme in the fed state. In space, the absence of gravity may tend to increase the transit rate along the small intestine by decreasing the dimensionless ratio of gravitational forces to viscous forces. In zero gravity, therefore, these alterations in GI emptying and intestinal transit rate could lead to erratic plasma levels and inefficient absorption.     

Biological effects of short-term feeding to rats of repeatedly used deep-frying fats in relation to fat mutagen content

The effects of short-term feeding of mutagen containing, heated deep-frying oils on urinary and faecal mutagenicity, plasma clinical biochemical parameters, peroxidative effects and cell proliferative indices in the gastro-intestinal tract were determined in rats. Repeatedly used frying oils [a saturated fatty acid-rich coconut oil (CO) and a polyunsaturated fatty acid (PUFA)-rich (greater than 60% PUFA) vegetable frying oil (PO)] were administered to groups of seven rats at a level of 10% (by weight) in the diet for 4 wk; control groups were fed equal amounts of the unheated oils. Both heated oils showed direct-acting mutagenicity to Salmonella tester strain TA97; heated PO was also mutagenic to strain TA100. Both heated CO and heated PO contained detectable amounts of thiobarbituric acid-reactive substances (TBA-RS). In heated PO, hydroperoxides of linoleic acid were also present. In groups fed heated oils the mutagenicity of urine and faeces to strain TA97 was not found to be increased in comparison with the control groups. Faecal mutagenicity to strain TA100 was also unaffected by consumption of heated oils. Urinary excretion of TA100 mutagens was significantly increased in rats fed heated PO. Plasma alkaline phosphatase activity was clearly raised in rats fed heated PO, in comparison with rats fed unheated oils or heated CO. In addition, other clinical biochemical plasma parameters showed a tendency to be increased in rats fed heated PO, indicating hepatic and renal cellular toxicity. Urinary and faecal excretion of thiobarbituric acid-reactive substances (TBA-RS) were also slightly, but not significantly, increased in rats fed heated PO. Feeding heated CO to rats did not result in increased plasma enzyme activities and excretion of TBA-RS, nor in increased cell proliferation in gastro-intestinal tissues. Cell proliferation of the oesophageal tissues were slightly, but significantly, increased in rats fed heated PO, in comparison with the group fed unheated PO. Tissues of the glandular stomach and colon/rectum did not show significantly enhanced cell proliferation in the group fed heated PO. The results obtained in this study indicated that consumption of heated oils containing TA100 mutagens and oxidation products of linoleic acid produced indications of cellular damage to liver and kidneys, and increased urine mutagenicity, as well as enhanced cell proliferation in the oesophagus.     

Effects of undernutrition on transit time and body weight of rats.

Rats given 50% and 25% of their ad lib food intake were taken as undernourished, while those on ad lib intake served as controls. Water was given ad lib for all rats. Body weight of all rats was measured daily. It showed decrease in undernourished groups but not to the extent expected from calorie intake. Fifty tiny (1-2 mm) orange coloured plastic markers mixed with food were given to all rats, at 11.00 p.m., and were collected from faeces at regular intervals of 1 h each till 80% of markers were obtained. Period (hrs) for collection of 80% markers was taken as total transit time. It showed increase with increased undernutrition (ad lib 38.9 +/- 2.1 hrs, 50% cal 68.2 +/- 5.3 hrs, 25% cal 105.00 +/- 3.3 hrs). Delayed transit time in the undernourished by prolonging contact period between food and absorptive surface of intestine probably caused increase in absorption of nutrients and thus counteracted against the loss in body weight of underfed rats.     

Pharmacological effects of oxytocin on gastric emptying and intestinal transit of a non-nutritive liquid meal in female rats

The effects of oxytocin (OT) on gastric emptying, gastrointestinal transit, and plasma levels of cholecystokinin (CCK) were studied in female rats. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na(2)(51)CrO(4). Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Blood samples were collected for CCK radioimmunoassay. After administration of OT (0.2-0.8 mg/kg), gastric emptying and gastrointestinal transit were inhibited, whereas the plasma concentration of CCK was increased in a dose-dependent manner. Atosiban, an oxytocin receptor antagonist, effectively attenuated the OT- induced inhibition of gastric emptying and gastrointestinal transit. However, administration of atosiban alone had no effect on gastric emptying and gastrointestinal transit. The selective CCK(1) receptor antagonists, devazepide and lorglumide, effectively attenuated the OT-induced inhibition of gastric emptying and gastrointestinal transit. L-365, 260, a selective CCK(2) receptor antagonist, did not alter the OT-induced inhibition of gastric emptying and gastrointestinal transit. These results suggest that OT inhibits gastric emptying and gastrointestinal transit in female rats via a mechanism involving CCK stimulation and CCK(1) receptor activation.     

Biochemical toxicology of argemone oil. IV. Short-term oral feeding response in rats

Consumption of edible oils contaminated with Argemone mexicana seed oil is known to cause various clinical manifestations. In the present study, the effect of dietary intake of argemone oil on histopathological changes, haematological indices and selected marker parameters of toxicity was investigated to observe the exact sites and mode of action of argemone oil in rats. Histopathological changes in the liver showed increased fibrosis, hyperplasia of bile ducts and congestion in a few portal tracts. Lungs of argemone oil-fed animals indicated congestion and thickening of interalveolar septa. Alveolar spaces were disorganised and irregular. Kidneys showed vascular and glomerular congestion and patchy tubular lesions. At 30 days only mild congestion was noted in the myocardium. Cardiac muscle fibres showed degenerative changes at 60 days which were more marked in the auricular wall. Haematological examination showed appearance of anaemia in experimental animals. Hepatic alkaline phosphatase, alanine transaminase and aspartate transaminase activities were inhibited by 30, 29 and 29% after 30 days of argemone intake along with concomitant enhancement in serum by 27, 29 and 66%, respectively. Liver showed decrease in glutathione (32-63%) content along with significant stimulation of lipid peroxidation (49-105%) in argemone-intoxicated animals. These results suggest that liver, lungs, heart and kidneys are the target tissues of argemone oil toxicity and that membrane destruction may be a possible mode of action.     

Evaluation of N-desmethylclozapine as a potential antipsychotic--preclinical studies.

There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT(2) antagonist and as a partial agonist to dopamine D(2) and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D(2) and 5-HT(2) receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT(2) (64-79%), but minimal D(2) occupancy (<15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.     

Effects of dl-fenfluramine and xylamidine on gastric emptying of maintenance diet in freely feeding rats

Freely feeding rats received an anorexigenic dose of dl-fenfluramine HCl (5 mg/kg). Two hours following injection, their stomachs retained significantly greater dry weight contents than saline-injected controls. The same dose of fenfluramine decreased the rate of gastric emptying over a 2 h period to a similar extent in mildly food-deprived rats. The peripherally acting serotonin antagonist xylamidine counteracted the effect of fenfluramine in prolonging the satiating effect of an ad libitum meal of a given size. We propose therefore that the principal mechanism by which fenfluramine reduces food consumption in freely feeding rats is through a prolongation of the satiating effect of absorption as a result of slowing of gastric emptying, presumably via enhanced release of serotonin from nerve terminals in the wall of the gastrointestinal tract.     

Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB(1) receptors

We studied the delay in gastric emptying and gastrointestinal transit induced by the cannabinoid receptor agonists (+)-WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) and CP 55,940 ((-)-cis-3[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol), as prevented by the selective cannabinoid CB(1)-receptor antagonist SR141716 ((N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide)) in rats after systemic or central drug administration. Oral SR141716 showed comparable potency (ID(50) range 1.0-3.9 mg/kg) in antagonizing gastric emptying and gastrointestinal transit delay by (+)-WIN 55,212-2 or CP 55,940. Gastric emptying and gastrointestinal transit delay after intracerebroventricular (i.c.v.) (+)-WIN 55,212-2 was prevented by oral or i.c.v. SR141716, but i.c.v. SR141716 did not significantly reduce the effect of i.p. (+)-WIN 55,212-2. Pertussis toxin prevented the delaying action of i.c.v. (+)-WIN 55,212-2 on both gastric emptying and gastrointestinal transit, but had no effect on (+)-WIN 55,212-2 i.p. These findings are consistent with a primary role of peripheral cannabinoid CB(1) receptor mechanisms in gastrointestinal transit delay by specific agonists.     

Anti-hyperlipidemic and cardioprotective effects of Ocimum sanctum L. fixed oil in rats fed a high fat diet

Ocimum sanctum (OS) has a lipid-lowering action in both normal and diabetic animals. Because OS leaves are rich in oil, the present study was conducted to explain the anti-hyperlipidemic and organ-protective effect of OS fixed oil in rats fed with a high fat (HF) diet. OS fixed oil was extracted by hexane and the fatty acids composition identified by GC-MS. Four groups of male Wistar rats included a normal control group, a high fat fed-diet (HF) group, a HF group treated with OS fixed oil, and a HF group treated with a reference drug simvastatin. The results show that OS fixed oil contains five kinds of fatty acids, of which alpha-linolenic acid was the major fatty acid. OS fixed oil depressed high serum levels of total cholesterol, triglyceride, LDL-C, and AI, whereas no significant effect on HDL-C was observed. OS fixed oil also suppressed high levels of liver cholesterol and triglyceride with no significant effect on both lipids in feces. In addition, OS fixed oil normalized the high serum levels of LDH and CK-MB but no significant effect on high serum levels of ALT, AST, and ALP was obtained. We conclude that treatment with OS fixed oil during the last three weeks of HF diet feeding decreased the high serum lipid profile and expressed antiartherogenic and cardioprotective actions against hyperlipidemia. The anti-hyperlipidemic action of OS fixed oil was mainly resulted from the suppression of liver lipid synthesis. Linolenic acid and linoleic acid contained in OS fixed oil were possibly responsible for both lipid-lowering and cardiac protective action against hyperlipidemia.     

Effect of anti-parkinsonism drugs on gastric emptying and intestinal transit in the rat.

The effect of atropine sulfate, trihexyphenidyl HCl, benztropine mesylate, diphenhydramine HCl and ethopropazine HCl on gastric emptying and intestinal transit of a phenol red solution in the rat was examined. Intraperitoneal administration of 0.3 mg/kg atropine, 1.2 mg/kg benztropine and trihexyphenidyl results in a marked decrease in gastric emptying and intestinal transit rate when compared to controls. Oral administration of these agents produced variable and unpredictable results. Single and multiple oral dose (0.6--3 mg/kg) studies with trihexyphenidyl failed to produce any significant decreases in gastric emptying rates. A single oral dose of benztropine (0.6--3 mg/kg) failed to reduce the gastric emptying rate, but multiple dose studies produced a significant decrease in the gastric emptying rate. Effects on gastric emptying and intestinal transit were seen after single and multiple oral doses of diphenhydramine and ethopropazine.     

Inhibition of gastric emptying and intestinal transit by amphetamine through a mechanism involving an increased secretion of CCK in male rats

1. The effect of amphetamine on gastrointestinal (GI) transit and the plasma levels of cholecystokinin (CCK) were studied in male rats.
2. Gastric emptying was inhibited both acutely and chronically by the administration of amphetamine. GI transit was decreased by the acute administration of amphetamine but not affected by the chronic administration of amphetamine.
3. Plasma CCK levels were increased dose-dependently by amphetamine.
4. Proglumide, a CCK receptor antagonist, prevented amphetamine-induced inhibition of gastric emptying and the decrease in GI transit in male rats.
5. The selective CCK_A receptor antagonist, lorglumide, dose-dependently attenuated the amphetamine-induced inhibition of gastric emptying in male rats. In contrast, the selective CCK_B receptor antagonist, PD 135,158, did not reverse the effect of amphetamine on gastric emptying.
6. Both lorglumide and PD 135,158 reversed the inhibitory effect of amphetamine on GI transit in male rats.
7. These results suggest that amphetamine-induced inhibition of gastric emptying and intestinal transit is due in part to a mechanism associated with the hypersecretion of endogenous CCK.

     

Acceleration of large intestine transit time in rats by sennosides and related compounds

Sennosides A + B and their natural metabolites, sennidins A + B, rheinanthrone and rhein, as well as the synthetic laxative danthron, were investigated for their influence on small and large intestine transit time in rats. Carmine red, as a marker, was administered through a gastric tube for small intestine transit or intracaecally by a chronically implanted catheter for colon transit. High doses of sennosides (250-500 mg kg-1) given orally from 20 min or up to 6 h before marker administration had no effect on small intestine transit time. The metabolites and danthron (10-100 mg kg-1 p.o.) also did not accelerate upper gastrointestinal passage. Intracaecal administration at the same time as carmine red, however, reduced the time for the appearance of the first coloured faeces from more than 8 h in the controls to 46 +/- 9 min after sennosides, 34 +/- 11 min after sennidins, 53 +/- 83 min after rhein and 16 +/- 4 min after rheinanthrone (50 mg kg-1 of each). Danthron was ineffective. Thus, sennosides and their natural metabolites specifically influence large intestinal motility. Acceleration of colonic transport seems to be a major component of the laxative action whereas for danthron motility changes are not responsible for its laxative action. Indomethacin partly inhibited the acceleration of large intestine transit induced by sennosides. An involvement of endogenous prostaglandins may therefore be possible, although a local bolus administration of PGF2 alpha or PGE2 into the caecal lumen neither influenced transit time nor induced diarrhoea.     

Dietary intake of rapeseed oil or soybean oil as the only fat nutrient in spontaneously hypertensive rats and Wistar Kyoto rats - blood pressure and pathophysiology

Spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were fed a diet containing 10% rapeseed (canola) oil or soybean oil as dietary fat, and given drinking water containing 1% NaCl for 26 weeks. From the 10th week and later, systolic blood pressure in the canola oil group became higher than that in the soybean oil group in each strain. The 26-week feeding of canola oil increased plasma lipids and the neutrophil counts, and decreased the platelet counts. In the canola oil group the heart and kidney tended to become heavier with sporadically found histologic lesions. Acetylcholine- and nitroprusside-induced dilating responses of isolated aortic rings and norepinephrine- and veratridine-induced increases in vascular tone of isolated perfused mesenteric arteries were not different between the two groups in each strain. These results demonstrate that canola oil intake as the only dietary fat elevates blood pressure of the rat provided with drinking water containing 1% NaCl through mechanisms other than blunt dilating response of the blood vessel due to dysfunction of the endothelium or vascular smooth muscle, the augmented response to norepinephrine in the arteries and the increased amount of norepinephrine in the sympathetic nerve endings. The lesions in the heart and kidney in SHR may be related to a strain-specific peripheral vascular deterioration which was disclosed by the extremely high blood pressure in the canola oil group.     

Effects of chronic celiprolol treatment on brown fat, feeding, and drinking in fa/fa Zucker rats

Celiprolol is a novel beta-adrenoceptor blocking drug that displays clinically favorable effects on glucose and lipid metabolism. Because some other atypical beta-adrenoceptor blocking drugs have been described to act as agonists on beta(3)-adrenoceptors, we aimed to investigate the effects of celiprolol on brown fat and beta(3)-adrenoceptors. Chronic treatment of obese fa/fa Zucker rats with celiprolol (50 mg/kg/day orally for 20 days) increased GDP binding to brown fat mitochondria by 1.5-fold, whereas beta(3)-adrenoceptor agonist ZD7114 ((S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyet hyl )phenoxyacetamide, 3 mg/kg/day) increased the binding by 3.3-fold. Weight gain was reduced by 19% due to decreased water and food intakes in celiprolol-treated rats. Celiprolol did not activate lipolysis in rat adipocytes in vitro or stimulate human beta(3)-adrenoceptors expressed in Chinese hamster ovary cells as measured with Cytosensor microphysiometer. Therefore, celiprolol does not seem to activate brown fat via beta(3)-adrenoceptors.