Oxotremorine-tolerance: muscarinic blockade or homeostatic adaptation?

Tremorine pretreatment of mice induces tolerance to some effects of oxotremorine. In the state of tolerance even the highest doses of oxotremorine did not cause antinociception, this blockade being insurmountable. Oxotremorine decreased motility and amphetamine hypermotility, and both effects were diminished by tremorine pretreatment. Amphetamine hypermotility increased in the tolerance state. The increase of cerebral acetylcholine level due to oxotremorine was diminished by tremorine pretreatment. It is suggested that a special blockade of cerebral muscarinic receptors might play a role in the tolerance phenomenon, moreover it is possible that some excitation develops in the CNS. A homeostatic adaptation may be involved a role in this kind of tolerance.     

Instrumental behavior in the activation or blockade of the neostriatum muscarinic receptors

In four dogs, microinjections of carbacholine enhanced the tonic component and inhibited the physical component of the instrumental defence reflex, put in order the posture, and increased its components' amplitude. Microinjections of raclopride yielded a similar though a less obvious result. Differentiation stimuli provided the greatest effect of both substances. A sharp improvement occurred in differentiation of sound signals. Microinjections of pyrenzepine yielded an opposite result. The data obtained are explained proceeding from the idea of a presence of the neostriatum's two efferent outputs exerting opposite effects on their targets, and the role of muscarine and dopamine receptors in their triggering and blockade.     

Effects of prior exercise on the thermic effect of glucose and fructose

It has been previously observed that the thermic effect of a glucose load is potentiated by prior exercise. To determine whether this phenomenon is observed when different carbohydrates are used and to ascertain the role of insulin, the thermic effects of fructose and glucose were compared during control (rest) and postexercise trials. Six male subjects ingested 100 g fructose or glucose at rest or after recovery from 45 min of treadmill exercise at 70% of maximal O2 consumption. Measurements of O2 consumption, respiratory exchange ratio, and plasma concentrations of glucose, insulin, glycerol, and lactate were measured for 3 h postingestion. Although glucose and fructose increased net energy expenditure by 44 and 51 kcal, respectively, over baseline during control trials, exercise increased the thermic effect of both carbohydrate challenges an additional 20-25 kcal (P less than 0.05). Glucose ingestion was associated with large (P less than 0.05) increases in plasma insulin concentration during control and exercise trials, in contrast to fructose ingestion. Because fructose, which is primarily metabolized by liver, and glucose elicited a similar postexercise potentiation of thermogenesis, the results indicate that the thermogenic phenomenon is not limited to skeletal muscle. These results also demonstrate that carbohydrate-induced postexercise thermogenesis is not related to an incremental increase in plasma insulin concentration.     

Eicosanoid and muscarinic receptor blockade abolishes hyperventilation-induced bronchoconstriction.

This study was designed to test the hypothesis that hyperventilation-induced bronchoconstriction (HIB) results from the combined effects of prostanoid and leukotriene metabolism. A bronchoscope was used in anesthetized dogs to record peripheral airway resistance and HIB before and after combined treatment with inhibitors of cyclooxygenase (indomethacin) and 5-lipoxygenase (MK-0591). Bronchoalveolar lavage fluid (BALF) cells and mediators from hyperventilated and control airways were also measured. Pretreatment with MK-0591 and indomethacin significantly attenuated, but did not abolish, HIB. However, addition of atropine nearly eliminated the residual response. Blockade of eicosanoid metabolism markedly reduced the concentrations of eicosanoids recovered in BALF after hyperventilation. Positive correlations between posthyperventilation BALF prostanoid and epithelial cell concentrations are suggestive of mucosal injury-induced mediator production and release. We conclude that HIB is prevented in the presence of eicosanoid and muscarinic-receptor blockade and that both classes of eicosanoids contribute similarly to the development of HIB.     

The effect of muscarinic and beta-adrenergic blockade on cysteamine-induced gastrin secretion by the isolated perfused rat stomach

Cysteamine-induced duodenal ulceration in rats is accompanied by increased circulating gastrin. Although cysteamine appears to exert a direct action on the gastrin cell some groups have provided evidence for an involvement of the autonomic nervous system. The current experiments were performed to determine whether beta-adrenergic or cholinergic (muscarinic) pathways are involved in the acute effect of cysteamine on gastrin secretion in the isolated perfused rat stomach. Cysteamine (1 mM) increased gastrin (IRG) secretion to a maximum ranging between 100% and 192% above basal. A cysteamine concentration of 5mM resulted in peak levels ranging between 150% and 1050% above basal. Addition of atropine or propranalol did not influence the responses obtained. The present results, therefore, do not support a role for either cholinergic or beta-adrenergic pathways in cysteamine-induced gastrin release at the level of the stomach and suggest that in vivo such autonomic effects are mediated extrinsically.     

Thermogenic response to insulin and glucose infusions in man: A model to evaluate the different components of the thermic effect of carbohydrate

The thermogenic response to an insulin and glucose infusion was determined in 10 healthy lean volunteers using a euglycemic clamp technique in conjunction with respiratory exchange measurements. The progressive rise in resting metabolic rate (RMR) from 4.295 ± 0.360 kJ/min during the baseline to 4.771 ± 0.410 kJ/min during the 90–120 min period of the euglycemic clamp (p < 0.01) correlated with the progressive increase in the glucose infusion rate (r = 0.836, p < 0.01), with the glucose storage rate (r = 0.812, p < 0.01), but not with the significant rise in insulin or norepinephrine concentrations. Storage of nutrients, as well as increased sympathetic nervous system (SNS) activity are known to increase RMR. Two thirds to three quarters of the observed increment in RMR following the insulin and glucose infusion in this study can be accounted for by the metabolic processing of the infused glucose for storage purposes. The rest of the thermogenic response (24–35%) must be explained by other mechanisms such as increased SNS activity.     

A comparison of benflurone effects after intravenous infusion or oral administration. A study on laboratory rats

The effects of oral administration and intravenous infusion of benflurone were compared using the single dose of 100 mg/kg b.w. Oral administration of benflurone induced more moderate changes in both white and red blood picture than the equal dose of orally administered cyclophosphamide. In contrast to oral benflurone administration, intravenous benflurone induced deep anaemia, deep reticulocytopenia, transient neutrophilia and slight decrease in small lymphocyte counts. The recovery from intravenous benfluorone effects was rapid.     

Compartmental mean residence time in a mammillary model with an effect compartment after intravenous or oral administration

A general estimation of mean residence time (MRT) in an effect compartment E, associated with a linear mammillary n-compartment model is presented: elimination takes place from the central and the effect compartments. Even though no sample is available from E, the MRT of the drug in this compartment can be estimated after intravenous or oral administation. Furthermore, the effect of MRT is independent of the route of administration. Also, with no new calculation, the method provides the area under the amount-time curve in compartment E.     

Effect of carbohydrate or carbohydrate plus medium-chain triglyceride ingestion on cycling time trial performance.

This study examined the effectiveness of ingesting a carbohydrate or carbohydrate + medium-chain triglycerides (MCT) on metabolism and cycling performance. Eight endurance-trained men [peak O(2) uptake = 4.71 +/- 0.09 (SE) l/min] completed 35 kJ/kg as quickly as possible [time trial (TT)] while consuming 250 ml/15 min of either a 6% (wt/vol) carbohydrate solution (C), a 6% carbohydrate + 4.2% MCT solution (C+M), or a sweet placebo (P). Time to complete the set amount of work was reduced in both C and C+M compared with P by 7 and 5%, respectively (C: 166 +/- 7 min; C+M: 169 +/- 7 min; P: 178 +/- 11 min; P < 0.01). Plasma glucose concentration was maintained at or above resting values throughout both C and C+M trials but decreased (P < 0.05) below resting values in P at the completion of the TT. The estimated rate of carbohydrate oxidation was not different during the first 90 min of exercise but thereafter was reduced (P < 0.05) in P and was maintained in both C and C+M. These data demonstrate that carbohydrate ingestion during exercise improves 100-km TT performance compared with a sweet placebo, but the addition of MCT does not provide any further performance enhancement.     

Influence of oral contraceptives on changes of the carbohydrate metabolism

Serum glucose and serum insulin levels were measured during oral glucose tolerance tests in 100 women, 20-39 years of age, who used the OC (oral contraceptive) preparation Stediril and in a control group of 96 women of the same age group. Significantly lower fasting serum glucose levels were observed after 6 months of OC use. Significant decreases in glucose tolerance were observed among OC users who had taken OCs for longer than 6 months. The blood glucose levels were elevated significantly in this group 60 and 120 minutes after the beginning of the test. No correlation could be found between age and changes in glucose tolerance. No significant differences in fasting serum insulin levels were found in either group. A significant increase in serum insulin levels was observed among women who had used OCs longer than 6 months; this increase was apparent only 120 minutes after the beginning of the test. These changes in glucose tolerance were found to be reversible. Glucose tolerance tests should be preformed once a year on OC users, more often if an abnormality in glucose metabolism, e.g. latent diabetes, is present.     

Effects of carbohydrate supplementation on performance and carbohydrate oxidation after intensified cycling training.

To study the effects of carbohydrate (CHO) supplementation on performance changes and symptoms of overreaching, six male endurance cyclists completed 1 wk of normal (N), 8 days of intensified (ITP), and 2 wk of recovery training (R) on two occasions in a randomized crossover design. Subjects completed one trial with a 6% CHO solution provided before and during training and a 20% solution in the 1 h postexercise (H-CHO trial). On the other occasion, subjects consumed a 2% CHO solution at the same time points (L-CHO). A significant decline in time to fatigue at approximately 63% maximal power output (H-CHO: 17 +/- 3%; L-CHO: 26 +/- 7%) and a significant increase in mood disturbance occurred in both trials after ITP. The decline in performance was significantly greater in the L-CHO trial. After ITP, a significant decrease in estimated muscle glycogen oxidation (H-CHO: N 49.3 +/- 2.9 kcal/30 min, ITP 32.6 +/- 3.4 kcal/30 min; L-CHO: N 49.1 +/- 30 kcal/30 min, ITP 39.0 +/- 5.6 kcal/30 min) and increase in fat oxidation (H-CHO: N 16.3 +/- 2.4 kcal/30 min, ITP 27.8 +/- 2.3 kcal/30 min; L-CHO: N 16.9 +/- 2.6 kcal/30 min, ITP: 25.4 +/- 3.5 kcal/30 min) occurred alongside significant increases in glycerol and free fatty acids and decreases in free triglycerides in both trials. An interaction effect was observed for submaximal plasma concentrations of cortisol and epinephrine, with significantly greater reductions in these stress hormones in L-CHO compared with H-CHO after ITP. These findings suggest that CHO supplementation can reduce the symptoms of overreaching but cannot prevent its development. Decreased endocrine responsiveness to exercise may be implicated in the decreased performance and increased mood disturbance characteristic of overreaching.     

The effect of carbohydrate on the structure and stability of erythropoietin.

Erythropoietin is a glycoprotein hormone that stimulates the maturation of late erythroid progenitor cells. It has three N-linked and one O-linked carbohydrates which play an important role in the biosynthesis and biological activities of the protein. To determine the role the carbohydrate might have in maintaining the conformational stability of the protein, the protein expressed in mammalian cells (fully glycosylated), the asialo mammalian-expressed protein, and the protein expressed in Escherichia coli (no carbohydrate) were compared for their stability to guanidine HCl, pH, and temperature. Circular dichroism was used to follow protein unfolding. Both the intact and asialo mammalian-expressed proteins unfolded with a cooperative transition in guanidine HCl, with a midpoint at 1.75 M guanidine HCl. The E. coli-expressed material unfolded with a midpoint of 1.2 M guanidine HCl, and a delta G of unfolding which was 1.4 kcal/mol less than that of the two glycosylated molecules. The E. coli-derived protein was also significantly less stable to pH-induced conformational changes, showing a cooperative transition in 35% glycerol with a midpoint at pH 4.4, while both the intact and asialo mammalian-expressed molecules had a transition midpoint of pH 3.75 in the absence of glycerol, and approximately pH 3 in the presence of 35% glycerol. The E. coli-expressed molecule unfolded and precipitated upon heating to 44 degrees C, while the asialo and intact mammalian-expressed proteins remained soluble, with a Tm of 56 degrees C. From these experiments, the carbohydrate appears to play a critical role in stabilizing the erythropoietin molecule to denaturing conditions, and this increased stability does not depend on the presence of sialic acid.     

The effect of thermic stress on the somatic reaction of rage and on rapid circling turns, in the cat.

An investigation was made of the effect of thermic stress on the somatic rage reaction and on rapid circling turns in cats awake and free to move in a behavioural cage. An increase in room temperature had a two-phase effect on the excitability of the nervous structures stimulated that is able to evoke the somatic rage reaction and rapid circling turns. The first phase, at room temperature 25 degrees-30 degrees C, was characterized by hypoexcitability; the second phase, appearing after longer periods of exposure and at temperatures above 30 degrees C, was characterized by the onset panting, hyperexcitability of the nervous structures stimulated and then by lowering of the somatic rage reaction threshold and a very significant increase in the number of circling turns. Experimentation on the action of cold external temperature on the excitability of structures involved in evoking the somatic rage reaction and rapid circling turns indicated an increase in their excitability, corresponding to an increase in spontaneous and evoked somatic motor activity.     

Over-reinforcement protects against memory deficits induced by muscarinic blockade of the striatum

It has been shown that blockade of muscarinic receptors of the anterior striatum (AS) induces significant impairments in the retrieval of stored information of a passive avoidance task, trained with conventional parameters of footshock, and that the same blockade is ineffective in altering short-term memory of this task. The results of the present experimental series showed that in conditions of over-reinforcement, microinjections of scopolamine into the AS shortly after training or before retention testing of passive avoidance, do not produce memory deficits when retention is assessed 30 min, 24 h or 48 h after training. It is suggested that after an enhanced learning experience (over-reinforcement) striatal cholinergic activity is not involved in short- and long-term memory functions.