Thermogenic and hormonal responses to palatable protein and carbohydrate rich food.

Simultaneous variations of oxygen consumption, and plasma insulin and norepinephrine were measured during the postprandial cephalic and gastrointestinal phases of feeding in six human subjects following the ingestion of various nutrients. On alternative days the subjects were given foods (1280 kjoules) either rich in carbohydrates (sugar pie) or in proteins (fish). Both nutrients produced an initial (0-40 min) enhanced thermogenesis and an early (2 min) cephalic insulin release. During that period, elevations of plasma norepinephrine were also observed with pie feeding at 10 and 30 min and at 10 min with fish. Palatability ratings indicated that both food items were equally tasting. During the gastrointestinal phase (40 to 120 min) the variations of these same parameters including glucagon seem to be explained by the content in carbohydrates and proteins in the food rather than by its palatability. Indeed during that period the protein meal was more thermogenic and the carbohydrate meal induced the expected insulin secretion. These results suggest that the palatability of the food is responsible for the early cephalic increase in postprandial thermogenesis, and for the insulin and norepinephrine release. During the subsequent gastrointestinal phase the increased thermogenesis is related to the composition of the food which exerts its action by the biochemical processes involved in the disposal of the absorbed nutrients.     

Thermogenic responses of high-altitude adapted rats on low temperatures and low pressures

The male rats were raised in two groups, one at Mt. Yatsugatake (2,100 m above sea level, the average ambient temperature 12.5 degrees C) for 30 days, and the other at a laboratory of Matsumoto (610 m above sea level, the average temperature 20 degrees C). The steady-state oxygen consumptions (VO2) and the rectal temperatures (TR) were measured under exposure conditions of various temperatures combined with different simulated altitudes. The values of VO2 and TR for a control group at 610 m-20 degrees C were regarded as 100% and the relative changes to the control values were obtained at various temperatures in the respective low-pressure condition. When measured at a simulated altitude of 2,000 m on the 2nd day after the rats raised at Mt. Yatsugatake were translocated to Matsumoto, the values at 0 degrees C and 10 degrees C room temperatures, VO2 and TR, were still significantly increased as compared with those of rats raised at Matsumoto. On the 40th day after the translocation from Mt. Yatsugatake, however, the values turned out to exhibit no significant difference in both groups. These results indicated that the greater thermogenesis of high-altitude adapted rats had been established by combined stimuli of low temperatures and low pressures as compared with those of Matsumoto-level adapted rats, but the responses returned to the control level by deadaptation process at 40 days after the translocation.     

Metformin restores responses to insulin but not to growth hormone in Sprague-Dawley rats

Administration of growth hormone (GH) increases muscle mass in F344 x BN rats, but not in Sprague-Dawley (S-D) rats. S-D rats are insulin-resistant and insulin responsiveness is required for the anabolic actions of GH. We hypothesized that correction of insulin resistance with metformin might also restore anabolic effects of GH. Treatment with GH (0.25 or 1.0 mg/kg twice daily for 9 days) had limited anabolic effects, reducing weight gain by 14%, increasing muscle glycogen content by 40% and increasing exercise capacity by 24%, but failing to increase muscle mass or to reduce fat mass. GH also impaired insulin responsiveness and increased visceral fat TNF content of visceral fat by 77%. Metformin enhanced insulin responsiveness in skeletal muscle, but failed to enhance anabolic effects of GH. Rats aged 14 weeks were treated for 21 days with metformin (320 mg/kg/day) and for the last 9 days, with GH (0.25 mg/kg, twice daily). Metformin caused a 2.3-fold increase in insulin-stimulated muscle glucose transport and a 20% reduction in muscle fatty acid oxidation, indicating increased glucose utilization. However, metformin did not augment GH-induced weight reduction. Metformin decreased visceral fat by 22% and subcutaneous fat by 20%, but no decreases were observed in the GH/metformin group. GH increased muscle glycogen by 40%, but the effect was reversed by metformin. VO(2max) was increased 24% by GH and 17% by metformin, but was not elevated in the GH/metformin group. GH increased TNF in visceral fat and the effect was augmented by metformin (144% increase). We conclude that metformin enhances some aspects of insulin responsiveness, but does not enhance anabolic responses to GH. The latter may, in part, be explained by the failure of metformin to prevent GH-induced elevation of TNF in visceral fat.     

Long-Evans and Sprague-Dawley rats exhibit divergent responses to refeeding after caloric restriction

Mature male Sprague-Dawley (SD) and Long-Evans (LE) rats were instrumented with telemetry transmitters for measurement of heart rate (HR) and housed in room calorimeters for assessment of food intake and oxygen consumption (Vo(2)) at standard laboratory temperatures (23 degrees C) to examine physiological responses to caloric restriction (CR; 60% of baseline ad libitum calories for 2 wk) and refeeding. Ad libitum controls had stable food intake (84-88 kcal/day) and gained weight at rates of 3-4 g/day. Groups from both strains assigned to CR exhibited similar patterns of weight loss and reductions in Vo(2) and HR. Upon refeeding, SD rats exhibited a mild, transient hyperphagic response (1 day) accompanied by sustained suppression of Vo(2) and HR that remained evident 8 days after refeeding. In contrast, LE rats exhibited sustained daily hyperphagia that persisted 8 days after refeeding and was accompanied by a complete restoration of HR and Vo(2). The lower HR and Vo(2) observed during refeeding in SD rats were not due to reduced locomotor activity. The results reveal a strain-dependent divergent response to recovery from CR. We conclude that during recovery from CR, homeostatic stimulation of appetite or suppression of energy expenditure may occur selectively to restore body weight.     

Sensitivity of adipocyte lipolysis to stimulatory and inhibitory agonists in hypothyroidism and starvation.

The responsiveness of lipolysis to the stimulatory agonists noradrenaline, corticotropin and glucagon and to the inhibitory agonists N6-phenylisopropyladenosine, prostaglandin E1 and nicotinic acid was investigated with rat white adipocytes incubated with a high concentration of adenosine deaminase (1 unit/ml). The cells were obtained from fed or 48 h-starved euthyroid animals or from fed or starved animals rendered hypothyroid by 4 weeks of treatment with low-iodine diet and propylthiouracil. Hypothyroidism increased sensitivity to and efficacy of all three inhibitory agonists in their opposition of noradrenaline-stimulated lipolysis. Starvation decreased sensitivity to all three inhibitory agonists when opposing basal lipolysis. Hypothyroidism decreased sensitivity to noradrenaline, glucagon and corticotropin by 37-, 4- and 4-fold respectively and decreased the maximum response to these agonists by approx. 50%, 50% and 75% respectively. Starvation reversed decreases in maximum response to these agonists in hypothyroidism. Starvation in the euthyroid state increased sensitivity to glucagon and noradrenaline, but did not alter sensitivity to corticotropin. Cells from hypothyroid rats were relatively insensitive to Bordetella pertussis toxin, which substantially increased basal lipolysis in the euthyroid state.     

Vascular responses to agonists in rat mesenteric artery from diabetic rats

The effect of diabetes on vascular smooth muscle function was investigated in the muscular arteries from spontaneously and chemically induced diabetic rats. Isolated ring segments of superior mesenteric arteries from BB diabetic and streptozotocin (STZ)-diabetic rats (12 weeks after onset of diabetes) were used for isometric tension studies. Contractile responses to alpha-adrenoceptor agonists (norepinephrine, methoxamine, phenylephrine, B-HT 920, guanabenz, SKF 89748-A), serotonin, and K+ were significantly higher in STZ-diabetic rat arteries as compared with the controls. In spontaneously diabetic rat arteries only the contractile responses to the putatively selective alpha 2-adrenoceptor agonists, K+ and prostaglandin E1, were significantly increased. pD2 values of the agonists in both groups of diabetic arteries were not significantly different from the respective controls. Nifedipine inhibited all contractile responses in a dose-dependent fashion. The responses to K+ and alpha 2-adrenoceptor agonists were attenuated to a greater extent by nifedipine in both groups of diabetic blood vessels. The calcium channel activator, BAY K 8644, produced a twofold increase in force of contraction in streptozotocin-diabetic and spontaneously diabetic rat arteries as compared with the responses in their respective controls. These results suggest caution in extrapolating all the findings from the streptozocin-induced diabetic model to the spontaneously diabetic model. However, increased activity of calcium channels in vascular muscle cells in both groups of diabetics may be responsible, at least in part, for the increased vascular contractility in diabetes mellitus.     

The effects of selective and nonselective cyclooxygenase inhibitors on endothelin-1-induced fever in rats

It was previously shown that sustained fever can be induced in rats by central injection of endothelin-1 (ET-1). This peptide appears to participate in the mechanism(s) of LPS-induced fever, which is reduced by pretreatments with ET(B) receptor antagonists. In this study, we compared the effects of a nonselective cyclooxygenase (COX) inhibitor, indomethacin, with those of two selective COX-2 inhibitors, celecoxib and lumiracoxib, on ET-1-induced fever in rats. Fever induced in conscious animals by ET-1 (1 pmol icv) or LPS (5 mug/kg iv) was prevented by pretreatments with celecoxib (5 and 10 mg/kg) or lumiracoxib (5 mg/kg) given by oral gavage 1 h before stimuli. Lower doses of celecoxib had partial (2.5 mg/kg) or no effect (1 mg/kg). Indomethacin (2 mg/kg ip) partially inhibited fever induced by LPS but had no effect on ET-1-induced fever. The levels of PGE(2) and PGF(2alpha) in the cerebrospinal fluid (CSF) of pentobarbital sodium-anesthetized rats were significantly increased 3 h after the injection of LPS or ET-1. The latter increase was abolished by celecoxib at all tested doses and by indomethacin. In conclusion, selective COX-2 inhibitors were able to prevent ET-1-induced fever, indicating a role for COX-2 in this phenomenon. However, the fact that reduced CSF PG levels obtained with indomethacin and a low dose of celecoxib are not accompanied by changes in fever induced by ET-1, along with the lack of inhibitory effects of indomethacin on ET-1 fever, suggests that the latter might also involve COX-2-independent mechanisms.     

Retinal dystrophy in Sprague-Dawley rats.

A spontaneous retinal dystrophy was found in 4 percent of Sprague-Dawley-derived rats examined. The lesion occurred both unilaterally and bilaterally in equal frequency, but the incidence in the females was 2 times greater than in males. Retinal change consisted of focal or diffuse absence of the outer layers of the retina, but frank degenerative changes or progression of the lesion was not observed. The cause of the dystrophy was not determined, but its increased occurrence with increasing age of the rats suggests an age-related lesion.     

Rotation in response to selective dopamine receptor agonists in rats with electrolytic substantia nigra lesions

Rats with unilateral, electrolytic substantia nigra (ESN) lesions were tested for rotation following systemic injections of the D1 dopamine receptor agonist SKF38393 or the D2 agonist quinpirole. Only quinpirole produced significant levels of rotation, which was ipsilateral in direction. This rotation was potentiated by coadministration of the D1 agonist, and was significantly reduced by injections of either a D1 or D2 receptor antagonist. Other groups of lesioned animals were treated with reserpine for 5 days and were then tested for rotation in response to the agonists. In this case, SKF38393 produced significant levels of contralateral rotation, while quinpirole-induced rotation remained ipsilateral; coadministration of the D1 and D2 agonists resulted in pronounced ipsilateral rotation. These results stress a role for D1 receptor mechanisms in producing rotation, and suggest that different striatal efferent pathways mediate rotation in response to selective agonists following ESN lesions.     

The effect of sex on central histaminergic responses and corticosterone bioperiodicity in Sprague-Dawley rats

Male and female rats demonstrate a difference in the relationship between food intake and H(1) receptor binding, which may be due to hormonal differences that exist. The relationship between the endocrine and histaminergic regulation and synchronization of food intake needs to be elucidated. Male and female rats fed 25% protein displayed bioperiodicity in mean corticosterone levels of 148.95+/-33.71 and 288.48+/-47.84 ng/ml, respectively. Accompanying bioperiodic times were of 22.43+/-1.35 h (males) and a period of 21.42+/-1.96 h (females). Central H(1) receptors in male rats had a mean bioperiodic value of 102.37+/-1.95 pmol/g protein with a period of 21.66+/-1.85 h, while that for females was 97.42+/-4.19 pmol/g protein with a period of 10.23+/-0.95 h. Central histaminergic activity affects feeding in rats with distinct gender variation that is bioperiodic in nature and functions as a major regulatory mechanism.     

Increased radiosensitivity of cerebral capillaries in neonatal Gunn rats as compared to Sprague-Dawley rats.

The extent of petechial haemorrhages of the cerebral cortex examined between 14 hours and 4 days after X-irradiation to the head was compared in Sprague-Dawley and homozygous Gunn rats with congenital hyperbilirubinaemia. Animals 1 to 2 days old received single doses of either 250, 500 or 750 rad. By means of a special scoring scale the degree of the damage to the microvasculature was semi-quantitatively estimated. In both strains a significant difference in effect was obtained between 250 and 500 rad, but not between 500 and 750 rad. The shape of the dose-effect curve in Gunn rats was similar to that of Sprague-Dawley rats, but displaced upwards. In Gunn rats the effect of 250 rad was greater than that of 750 rad in Sprague-Dawley rats. Possible radiosensitizing mechanisms are discussed with reference to the literature and our results.     

Effect of selective muscarinic receptor agonists and antagonists on active-avoidance learning acquisition in rats

Effect of some selective muscarinic receptor agonists and antagonists was investigated on learning acquisition in an active-avoidance paradigm in rats which records an anticipatory conditioned avoidance apart from the classical conditioned avoidance response. The muscarinic M1 agonists, arecholine, pilocarpine and McN-A-343, facilitated learning acquisition, which was attenuated by the selective M1 antagonist, pirenzepine. On the other hand, M2 receptor agonist, carbachol, and physostigmine, induced a dose-related dual response, with lower doses retarding and higher doses facilitating the learning acquisition. The former effect was attenuated by gallamine, a muscarinic M2 antagonist, while the latter response was inhibited by pirenzepine, indicating that these putative M2 receptor agonist lose their receptor specificity on dose increment. The selective M2 receptor antagonists, gallamine and AF-DX 116, facilitated learning acquisition, which was inhibited by pirenzepine and the acetylcholine synthesis inhibitor hemicholinium. The results support the cholinergic hypothesis of learning and memory and indicate that M1 receptor agonists and M2 receptor antagonists are likely to prove beneficial in memory deficits. The data also indicates that the clinical dose of some drugs, like physostigmine, needs to be carefully established for optimum therapeutic benefit.     

Spontaneous neoplastic lesions in aged Sprague-Dawley rats.

Neoplastic lesions were observed in untreated aged Sprague Dawley (SD) rats throughout their lifespan starting at 5 weeks. Their mean survival times were 89 to 105 weeks of age. The total tumor incidences were 70 to 76.7% and 87 to 95.8% in males and females, respectively. The common neoplasmas were pituitary adenoma and adrenal pheochromocytoma in both sexes, testicular Leydig cell tumor in males and mammary gland tumors, thyroidal C-cell adenoma and uterine stromal polyp in females.     

Dextran anaphylactoid reaction in Sprague-Dawley CFY rats.

From a closed colony of randomly-bred Sprague-Dawley CFY rats about 23% failed to respond to intravenous dextran with the characteristic generalized anaphylactoid reaction, but still exhibited an inflammatory response when dextran was given into the foot pad. Brother-sister mating of rats showing the most expressed generalized reaction (reactor rats) yielded good responder offsprings, while the non-reactors had descendants completely unresponsive to systemic dextran. Brother-sister mating of selected non-reactor rats led to a gradual decrease in dextran paw oedema in the subsequent generations, and after the third mating, a complete local non-reactivity developed. In these rats the intradermal injection of dextran failed to increase vascular permeability, while the inflammatory response evoked by histamine, 5-HT, bradykinin, and compound 48/80 remained unchanged as compared to that of the reactor animals. These result show that the anaphylactoid reaction in Sprague-Dawley CFY rats is under genetic control.     

Withdrawal and bidirectional cross-withdrawal responses in rats treated with adenosine agonists and morphine

The aim of this study was to investigate whether the A1/A2 receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), and the selective A1 agonist, N6-cyclopentyladenosine (CPA), induced physical dependence by quantifying specific antagonist-precipitated withdrawal syndromes in conscious rats. In addition, the presence of bidirectional cross-withdrawal was also investigated. The agonists were administered s.c. to groups of rats at 12 h intervals. Antagonists were administered s.c., 12 hours after the last dose, followed by observation and measurement of faecal output for 20 min. NECA (4 x 0.03 mg kg(-1), s.c) and CPA (4 x 0.03, 0.1 and 0.3 mg kg(-1), s.c.) induced physical dependence, as shown by the expression of a significant withdrawal syndrome when challenged with the adenosine A1/A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 0.1 mg kg(-1), s.c.) and the A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPDPX, 0.1 mg kg(-1), s.c.) respectively. The syndromes consisted of teeth chattering and shaking behaviours shown to occur in morphine-dependent animals withdrawn with naloxone viz, paw, body and 'wet-dog' shakes, but with the additional behaviours of head shaking and yawning. In further contrast to the opiate withdrawal syndrome, no diarrhoea occurred in the groups of animals treated with adenosine agonists and withdrawn with their respective antagonists. Bidirectional cross-withdrawal syndromes were also revealed when naloxone (3 mg kg(-1), s.c.) was administered to adenosine agonist pre-treated rats and adenosine antagonists were given to morphine pre-treated rats. This study provides further information illustrating that close links exist between the adenosine and opiate systems.     

Some characteristics of the insulin-induced potentiation to anaphylactoid reaction in Sprague-Dawley rats.

The insulin-induced sensitization to generalized and local anaphylactoid reaction evoked by dextran was studied in Sprague-Dawley CFY rats. The generalized reaction was shown to be potentiated by insulin given subcutaneously in a dose-related manner. The minimum effective dose was as low as 0.04 U/kg. When this dose was injected intravenously, a marked but short-lived potentiation was observed. The insulin response could be elicited throughout the whole year. The local oedema induced by subplantar injection of dextran was found to be much less sensitive to insulin. Potentiation was observed during the period from March to October, while in the intermediate months, no such effect could be seen. The seasonal refractory state to insulin was abolished by bilateral adrenalectomy, and daily pretreatment of the rats with insulin for several days. Actinomycin D prevented the restorative effect of insulin pretreatment. Sensitization by a single insulin dose to both systemic and local dextran was suppressed in rats older than 6 months, and the refractoriness was in part reversed by adrenalectomy.     

Thermogenic and anorectic effects of ephedrine and congeners in mice and rats

(?)-Ephedrine has been shown to increase energy expenditure and cause the loss of body fat in rats and mice. The present study compares the effects of (?)- and (+)-ephedrine, (?)- and (+)- pseudoephedrine, (±)- and (+)-norephedrine and (?)- and (+)-norpseudoephedrine on food intake, energy expenditure and body composition in $\text{ob}$/$\text{ob}$ and normal mice and food intake in rats. The most potent anorectic and thermogenic compounds had the S configuration at the C-2 position but the orders of potencies for the compounds for anorexia and thermogenesis were not identical. The potencies of the compounds in reducing body lipid content correlated better with their thermogenic than their anorectic potencies.