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Biomedical subjects

M J Stock

Publications and source records attributed to M J Stock.

At least 19 recordsLinked to original sources
PubMed1997

Sibutramine: a review of the pharmacology of a novel anti-obesity agent.

Sibutramine is a noradrenaline and 5-hydroxytryptamine reuptake inhibitor which causes weight loss in laboratory rodents via effects on both food intake and metabolic rate. Sibutramine's effects are predominantly mediated by two pharmacologically-active metabolites (its primary and secondary amines). Sibutramine and its active metabolites do not cause the release of monoamine neurotransmitters and do not have affinity for their receptors. Sibutramine dose-dependently inhibits 24 h food intake in rats by enhancing the natural physiological process of satiety. Sibutramine also stimulates thermogenesis in rats, producing sustained (> 6 h) increases in oxygen consumption of up to 30%. The thermogenic effect of sibutramine results from central activation of efferent sympathetic activity which, in turn, involves activation of beta 3-adrenoceptors. Sympathetic stimulation of brown adipose tissue via beta 3-adrenoceptors is thought to be the cause of the large, 18 fold increase in brown adipose tissue glucose utilization induced by sibutramine. These dual effects of sibutramine on food intake and thermogenesis explain its anti-obesity effect in animals.

Adipose Tissue, Brown↗
PubMed1996

Effect of selective beta-adrenoceptor stimulation on UCP synthesis in primary cultures of brown adipocytes.

Given the co-existence of the three beta-adrenoceptor (beta AR) subtypes (beta 1AR, beta 2AR and beta 3AR) in brown adipocytes, the present study was undertaken to determine the relative importance of these in the induction of UCP synthesis in mouse BAT precursor cells in primary culture. Cells at different stages of differentiation were exposed to different beta AR agonists: prenalterol (a selective beta 1AR agonist), salbutamol or clenbuterol (selective beta 2AR agonists), or BRL 37344 (a selective beta 3AR agonist). As with the endogenous agonist, noradrenaline, and the non-selective beta AR agonist, isoprenaline, all four beta AR agonists induced UCP in the confluent stage of the cells, but with different potencies, and with the highest induction being seen after clenbuterol or BRL 37344 treatment. Cells in the confluent stage of development were the most sensitive to the effects of the agonists, although clenbuterol and BRL 37344 induced a weak UCP synthesis in pre-confluent cells. None of these beta AR agonists were able to induce UCP synthesis in the post-confluent period. The responses to prenalterol and salbutamol were inhibited by propranolol at relatively low concentrations, suggesting their effects were mediated by beta 1AR and beta 2AR, respectively. However, propranolol was a particularly weak antagonist of BRL 37344 and, unexpectedly, of the clenbuterol UCP responses, which suggests that both induce UCP synthesis via the beta 3AR. In summary, the beta 3AR is the most important adrenoceptor coupled to the induction of UCP synthesis, although both beta 1AR and beta 2AR activation may make a contribution. However, all three beta AR subtypes do not become fully functional until cultured cells become confluent.

Adipose Tissue, Brown↗
PubMed1996

Temperature-dependent effects of ephedrine in the cold.

This experiment examined the effects of intraperitoneal ephedrine (5-25 mg/kg) on operant thermoregulatory behavior of rats in the cold (-8 degrees C), and of 10 mg/kg on metabolic rate at a thermoneutral (22 degrees C) ambient temperature (Ta) and in the cold (5 degrees C). Posttest colonic temperature (Tc) decreased dose-dependently in the behavioral tests, yet the demand for heat varied little with respect to saline except for a significant reduction at the lowest dose tested (i.e., there was no compensation for the reduced Tc induced by ephedrine). Ephedrine had a potent thermogenic effect at a Ta of 22 degrees C, increasing both metabolic rate and Tc. In the cold, ephedrine reduced Tc, but this effect could not be accounted for by a reduction in metabolism, which was not significantly different from saline.

Animals↗
PubMed1996

Biphasic effects of the beta-adrenoceptor agonist, BRL 37344, on glucose utilization in rat isolated skeletal muscle.

1. The effects of the selective beta 3-adrenoceptor agonist, BRL 37344 (BRL) on glucose uptake and phosphorylation (i.e. glucose utilization; GU) and glycogen synthesis in rat isolated soleus and extensor digitorium longus (EDL) muscle preparations in vitro were investigated by use of 2-deoxy-[3H]-glucose (GU) and [U-14C]-glucose (glycogen synthesis). 2. Low concentrations of BRL (10(-11)-10(-9) M) significantly increased GU, with maximal increases of 30% in soleus and 24% in EDL at 10(-11) M. Neither the selective beta 1-adrenoceptor antagonist, atenolol (10(-8)-10(-6) M), nor the selective beta 2-adrenoceptor antagonist, ICI 118551 (10(-8)-10(-6) M) had any effect on the stimulation of GU induced by 10(-11) M BRL. 3. High concentrations of BRL (10(-6)-10(-5) M) caused significant inhibition (up to 30%) of GU in both soleus and EDL muscles. The inhibition of 10(-6) M BRL was blocked completely by 10(-6) and 10(-7) M ICI 118551 in soleus, and by 10(-6)-10(-8) M ICI 118551 in EDL; atenolol (10(-8)-10(6) M) had no effect. 4. Another selective beta 3-adrenoceptor agonist, CL 316,243, also caused a significant stimulation of muscle GU, with maximal increases of 43% at 10(-9) M in soleus and 45% at 10(-10) M in EDL. The stimulation of GU declined with further increases in the concentration of CL 316,243, but no inhibition of GU was seen, even at the highest concentration (10(-5) M) tested. 5. BRL at 10(-5) M inhibited completely insulin-stimulated glycogen synthesis in both soleus and EDL, but this inhibitory effect of BRL was abolished by 10(-6) M ICI 118551. BRL at 10(-11) M (with or without 10(-6) M ICI 118551) had no effect on insulin-stimulated glycogen synthesis. 6. It is concluded that: (i) low (< nM) concentrations of BRL stimulate GU via an atypical beta-adrenoceptor that is resistant to conventional beta 1-adrenoceptor and beta 2-adrenoceptor antagonists; (ii) the stimulation of GU is negated by the activation of beta 2-adrenoceptors that occurs at higher (> nM) concentrations of BRL; (iii) inhibition of GU via beta 2-adrenoceptor activation is associated with inhibition of glycogen synthesis, possibly due to activation of glycogenolysis; (iv) the opposing effects of beta 2-adrenoceptor and atypical beta-adrenoceptor activation on GU suggest that in skeletal muscle these adrenoceptors are linked to different post-receptor pathways.

Adrenergic beta-Agonists↗
PubMed1996

Inhibition of brown fat activity during hypothalamic stimulation in the rat.

Previous work has shown that low-level electrical stimulation of the ventromedial hypothalamus (VMH) in anesthetized rats produces a sustained decrease (phase 1) in interscapular brown adipose tissue (IBAT) temperature followed by a rise (phase 2) after the stimulus has stopped [Woods, A. J., and M. J. Stock. Am. J. Physiol. 266 (Regulatory, Integrative Comp. Physiol. 35): R328-R337, 1994]. In this study, rat oxygen consumption was found to decrease (24%) and then increase (74%) during phase 1 and 2, respectively. The effect of norepinephrine, alpha-adrenoceptor antagonists, substance P, and neuropeptide Y, with and/or without VMH stimulation, suggested that vasoconstriction was unlikely to account for the phase 1 decreases in thermogenesis and temperature. However, measurement with radio-labeled microspheres showed that IBAT capillary blood flow was reduced by 70% during phase 1, and this, plus a 50% decrease in blood oxygen extraction, indicated that phase 1 could be due to vasodilatation of arteriovenous anastomoses. It was postulated that phase 1 resulted from release of neuropeptides, such as substance P, causing diversion of arterial blood away from IBAT capillaries, thereby increasing convective heat loss and inhibiting heat production during phase 1.

Adipose Tissue, Brown↗
PubMed1996

Effect of clenbuterol on growth and body composition during food restriction in rats.

Clenbuterol was administered as a dietary admixture (4 mg/kg diet) to three groups of male Wistar rats (n = 8) housed individually in metabolism cages and fed for 15 d at 110, 160, and 235% (ad libitum) of estimated requirement for energy maintenance. Untreated groups at each level of energy intake were also included. There was no effect of clenbuterol on food intake in the ad libitum group, but the drug produced significant increases in body weight, feed efficiency, and carcass weight, dressing and protein content at all three levels of energy intake. This effect of clenbuterol was particularly noticeable in the restricted animals. Clenbuterol caused changes in body composition (increased percentage of water and protein, decreased percentage of fat) in the ad libitum rats but had no effect in the restricted groups. The reduction in the growth of the viscera caused by energy restriction was not affected by clenbuterol, apart from in the 110% restricted group, where the gastrointestinal tract was 26% heavier in the clenbuterol-treated rats. The results show that the growth anabolic actions of clenbuterol can be sustained and may be even more marked in rats fed restrictively than in those given ad libitum access to feed.

Adrenergic beta-Agonists↗
PubMed1996

Relationship between feeding pattern and body mass index in 220 free-living people in four age groups.

OBJECTIVE: To assess the relationship between feeding pattern and body mass index in free-living humans. DESIGN AND SUBJECTS: Feeding pattern was assessed from 220 7-day weighed dietary records. 187 records were obtained from three separate existing studies, and reanalysed. These studies contained data on three age groups in the British population; Elderly group (n = 88), Middle-aged group (n = 40), Working age group (n = 59). A separate study of 13-14 year olds living in Croydon was conducted from which 33 usable diet records were collected to produce a fourth, Adolescent group. RESULTS: 'Nibbling' and greater energy intakes at breakfast were associated with a lower body mass index (BMI) in the Adolescent group. In the Middle-aged group, greater energy intakes at breakfast and lower energy intakes during the evening were associated with a lower BMI. However, when diet records which produced unreasonably low energy intakes were removed from the analysis, these relationships disappeared except for energy intakes at breakfast and BMI in the Adolescent group. CONCLUSION: It is suggested that the relationship between feeding pattern and BMI observed in the Adolescent and Middle-aged groups was caused by underestimation of 'habitual' energy intake from snacks and the omission of breakfast by females and those who were overweight. The lack of relationship in the Working age group was attributed to the fact that more individuals in this group appeared to report valid diet records. Reported energy intake was directly related to BMI in the Working age group, but was not related to BMI in the other three age groups. It is concluded that feeding pattern is not a major factor in determining BMI in humans. Also, since snacks have a relatively high sugar and low fat composition compared with meals, it is suggested that biased under-reporting of snacks by the obese could produce spurious results from free-living studies which show that obesity is related to the proportion of energy from fat in the diet.

Adolescent↗
PubMed1995

Effects of clenbuterol and salbutamol on tissue rubidium uptake in vivo.

In anesthetized rats, injection of the beta 2-adrenoceptor (beta 2-AR) agonist clenbuterol (0.45 mumol/kg) caused a marked stimulation of 86RbCl (Rb) uptake by skeletal muscle, but had no effect on other tissues; soleus muscle showed the largest (144% increase) response. Injection of another beta 2-AR agonist (salbutamol 0.45 mumol/kg) had no effect on Rb uptake by any tissue except soleus muscle (83%). Both agonists increased body (colonic) temperature to the same extent. A 3-day treatment with salbutamol as a dietary admixture had no effect on body weight, muscle mass, or tissue Rb uptake, whereas the same treatment using clenbuterol produced significant increases in body weight and muscle mass and significant decreases in Rb uptake in three of the four muscle groups studied; Rb uptake in soleus was not affected. In another experiment, the short-term effect of clenbuterol injection on muscle Rb uptake was found to be resistant to a high dose (20 mg/kg) of the selective beta 2-AR antagonist ICI 118551. It was concluded that the selective effects of short-term administration of clenbuterol on muscle Rb uptake, coupled with its effects over 3 days on Rb uptake and muscle hypertrophy, implicate beta-AR modulation of cation transport (possibly via Na,K-adenosine triphosphatase [ATPase] activity) in the anabolic effects of clenbuterol on muscle protein deposition. Since the stimulation of Rb uptake by clenbuterol was resistant to high doses of a selective beta 2-AR antagonist and since salbutamol had little or no effect on muscle hypertrophy or Rb uptake, it is suggested that clenbuterol may exert its effects via an atypical beta-AR.

Adipose Tissue, Brown↗
PubMed1995

Acute effects of the beta 3-adrenoceptor agonist, BRL 35135, on tissue glucose utilisation.

1. The acute effects of BRL 35135 (BRL) on tissue glucose utilisation index (GUI) in vivo were investigated in anaesthetized rats by use of 2-deoxy-[3H]-glucose. 2. Intravenous injection of BRL caused a dose-dependent increase in GUI in skeletal muscle, and white and brown adipose tissue; plasma insulin and fatty acid concentrations were also increased. Chronic treatment with BRL added to the diet caused a 34 fold increase in basal GUI of brown adipose tissue (BAT), but had no effect on GUI in other tissues. After chronic treatment, the acute tissue response to an intravenous maximal dose of BRL had disappeared completely in all tissues apart from the soleus muscle. 3. A high dose (20 mg kg-1) of the non-selective beta-antagonist, propranolol, inhibited the acute effect of BRL on GUI in BAT, but failed to affect GUI in muscle. A lower dose (1 mg kg-1) of the antagonist also inhibited the BAT response, but had little or no effect on the response in Type I (working) muscles such as soleus and adductor longus (ADL), and potentiated the response in Type II (non-working) muscles such as tibialis and extensor digitorium longus (EDL). 4. A low dose (1 mg kg-1) of the selective beta 1-antagonist, atenolol, had no effect on the BRL response but the same dose of the selective beta 2-antagonist, ICI 118551, potentiated significantly the effect of BRL on GUI in most muscles without altering plasma insulin levels. 5. It is concluded that: (i) the heterogeneous tissue responses of different muscle fibre types in the presence of P-antagonists indicates that BRL affects muscle GUI directly, in addition to effects mediated by increases in plasma insulin concentration; (ii) the resistance of the BRL response to conventional P-adrenoceptor antagonists implicates an atypical adrenoceptor mediating the GUI response in skeletal muscle, but this may not be identical to the adipose tissue P3-adrenoceptor; (iii) the potentiation of BRL responses by ICI 118551 indicates an inhibitory P2-adrenoceptor-mediated component in the muscle GUI response to BRL.

Adipose Tissue↗
PubMed1995

Sources of energy from meals versus snacks in 220 people in four age groups.

OBJECTIVES: To assess meals versus snacks in terms of their contribution to total daily energy intake (TDI), macronutrient composition, and food commodity profile. DESIGN AND SUBJECTS: Meals and snacks were assessed from 220 7-day weighed dietary records. 187 records were obtained from three separate existing studies, and reanalysed. These studies contained data on three different age groups in the British population; elderly group (n = 88), middle-aged group (n = 40), young adult group (n = 59). A separate study of 13-14-year-olds living in Croydon was conducted from which 33 usable diet records were collected (adolescent group). RESULTS: Boys in the adolescent group consumed more of their TDI as snacks (29.0%) compared with men in the young adult (18.9%) and elderly groups (16.6%), but not the middle-aged group (25.8%). Females consumed about the same percentage of their TDI as snacks; adolescent group 23.6%, young adult group 19.4%, middle-aged group 21.4%, elderly group 17.9%. Meals were higher in protein and fat, and lower in total sugars, compared with snacks. Chocolate confectionery, crisps and fizzy drinks and squashes were popular snack foods in the adolescent group. Unlike snacks, the food commodity profiles of meals were similar in all age groups. CONCLUSIONS: This study shows that foods and drinks consumed as snacks by the British public, including the elderly, have a relatively high total sugar composition. These results add to the concern relating snack foods with dental caries.

Adolescent↗
PubMed1995

Differences in conicity in young adults of European and south Asian descent.

A survey of 320 (175 male, 155 female) 19 year-old medical students showed that male students of South Asian origin in the top tertile for body weight or body mass index had a significantly greater conicity index than European males in these top tertiles. This difference in conicity was not significant in the group as a whole, or when ethnic pairs were matched for body weight or body mass index. However, females of South Asian descent had a significantly higher conicity index than females of European descent irrespective of how the groups were compared. The trend towards higher conicity (i.e. abdominal obesity) in young Asians may help explain the higher incidence of diabetes and cardiovascular disease seen in elderly Asians living in the United Kingdom.

Adult↗
PubMed1995

Contribution of beta 3-adrenoceptor activation to ephedrine-induced thermogenesis in humans.

OBJECTIVE: To investigate the contribution of beta 3-adrenoceptor activation to sympathetic stimulation of thermogenesis in humans using a sympathomimetic (ephedrine) in combination with a non-selective beta-adrenoceptor antagonist (nadolol). DESIGN: Three doses (2.5, 5 and 10 mg) of nadolol were used to estimate what fraction of the thermogenic response to ephedrine (30 mg) remained after inhibition of beta 1- and beta 2-adrenoceptor mediated responses. SUBJECTS: Nine healthy, young male volunteers at rest after an overnight fast. MEASUREMENTS: Energy expenditure, respiratory quotient, heart rate, blood pressure and plasma potassium, glucose, lactate, glycerol, NEFA and triglycerides were measured before, and for 3 h after treatment with placebo, ephedrine and ephedrine plus three doses of nadolol. RESULTS: Ephedrine produced significant increases in energy expenditure (thermogenesis), heart rate, systolic blood pressure and plasma glucose; the other parameters measured did not change significantly. Nadolol caused significant inhibition of all responses, but 43% of the thermogenic response to ephedrine remained after the 2.5 mg dose of nadolol, whereas the same dose completely inhibited the heart rate and plasma glucose responses. CONCLUSION: All three beta-adrenoceptor subtypes (beta 1, beta 2 and beta 3) may be involved in ephedrine-induced thermogenesis, but the resistance to complete inhibition by the non-selective antagonist nadolol indicates that at least 40% of the response is mediated by an atypical receptor, which is presumed to be the beta 3-adrenoceptor.

Adrenergic beta-Antagonists↗
PubMed1994

Thermoregulatory effects of resiniferatoxin in the rat.

When administered acutely, the vanilloid (capsaicin) receptor agonist resiniferatoxin induces marked hypothermia in the ferret, rat and mouse. The aim of this study was to further characterise the thermoregulatory effects of resiniferatoxin in the rat in an attempt to understand the mechanism by which resiniferatoxin induces this hypothermic effect. Three doses of resiniferatoxin were administered (50, 100, 200 micrograms/kg s.c.) in separate animals at an ambient temperature (Ta) of 20 degrees C but there was no apparent dose-related effect on the decrease in colonic temperature over this range. Resiniferatoxin (50 micrograms/kg s.c.) decreased whole body oxygen consumption when measured below thermoneutrality (Ta = 20 degrees C) but not at thermoneutrality (Ta = 29 degrees C); likewise there was no hypothermic response to resiniferatoxin when measured at a Ta of 29 degrees C. Operant responding for radiant heat in a cold environment (-8 degrees C) was also measured in resiniferatoxin-treated (50 micrograms/kg s.c.) rats. These experiments showed that resiniferatoxin-treated rats attempted to defend body temperature by lever pressing for more radiant heat. However, this was not sufficient to reverse the hypothermia. Two repeat doses, 1 week apart, had little or no effect on colonic temperature, oxygen consumption or operant responding in the cold. Resiniferatoxin (50 micrograms/kg s.c.) also produced hypothermia (Ta = 20 degrees C) in neonatally capsaicinized adult rats. The exact site and mode of action is still under investigation, but it is postulated that resiniferatoxin activates, and then destroys or desensitizes warm thermoreceptors.

Animals↗
PubMed1994

Anabolic effects of clenbuterol after long-term treatment and withdrawal in t the rat.

Injection of rats with the beta 2-adrenoceptor agonist clenbuterol (1 mg/kg/d for 15 days) stimulated an increase in body weight (9%) and protein (8%) and water (7%) content, but reduced food intake (4%) and epididymal fat pad mass (39%). Nine days after termination of treatment, ex-clenbuterol rats were heavier (5%) and had a greater protein (7%) and water (6%) content and lower fat pad mass (32%) than controls. Clenbuterol-fed rats (2 mg/kg diet for 10 days, providing an average of 0.04 mg clenbuterol/kg/d) increased body weight (7%), muscle mass (15% to 21%), and muscle protein content (9% to 26%), whereas epididymal fat pad weight and muscle glycogen content were reduced. During the withdrawal period, the greater body weight of ex-clenbuterol rats was sustained overall (ANOVA, P < .00005), but by day 10 this difference was no longer significant. At this point, gastrocnemius muscle mass was still higher (11%) when compared with that of control animals, but soleus muscle mass, muscle glycogen concentration, and epididymal fat pad weight had reverted to control values. These results were corroborated in a subsequent experiment using older rats. It was concluded that, unlike other beta-adrenoceptor-mediated effects, muscle protein accumulated during clenbuterol treatment can be maintained in certain muscles after removal of the drug for a period of time that is at least equivalent to the duration of treatment. This could have implications for the potential therapeutic use of this class of compound, and differences in the response observed between muscle types may help to elucidate the mechanisms responsible for the muscle protein deposition induced by clenbuterol.

Adipose Tissue↗
PubMed1994

Effects of digoxin on the anabolic response to clenbuterol.

The possible involvement of increased cation exchange in the anabolic response to the beta 2-selective adrenergic agonist clenbuterol was investigated using dietary admixtures of clenbuterol and the Na,K-adenosine triphosphatase (ATPase) inhibitor digoxin. In a rat feeding trial to assess the effects on body composition, it was found that the higher of two levels (5 and 30 mg/kg diet) of digoxin had an inhibitory effect on the repartitioning effects (ie, increased body weight and fat-free mass) of clenbuterol (2 mg/kg diet). In two further experiments using 30 and 60 mg digoxin/kg diet, it was found that the anabolic effects of clenbuterol on gastrocnemius muscle protein deposition were inhibited by digoxin, but the effects of clenbuterol on soleus muscle protein were more resistant to inhibition. Given the observed dose-dependent inhibition by digoxin of gastrocnemius muscle protein deposition in the three experiments, it was concluded that at least part of clenbuterol's anabolic actions on skeletal muscle may depend on increased Na,K-ATPase activity. However, different mechanisms or a different time course of Na,K-ATPase activation may occur in different muscle fiber types.

Analysis of Variance↗
PubMed1994

Biphasic brown fat temperature responses to hypothalamic stimulation in rats.

Low-level electrical stimulation (monophasic square-wave pulses: 15 Hz, 7.0 microA, 0.5 ms) of the ventromedial hypothalamus (VMH) in anesthetized rats produced a decrease (phase 1) in interscapular brown adipose tissue (IBAT) temperature that was sustained for as long as the stimulus was applied (2-45 min). A rise in IBAT temperature (phase 2) occurred only after the stimulation had stopped. VMH stimulations ipsilateral and contralateral to a lateral hypothalamic (LH) lesion indicated that the phase 1 response required an intact LH, and denervation of IBAT showed that both phases required an intact sympathetic innervation. Central intracerebroventricular injections of amphetamine and dopamine produced decreases in IBAT temperature similar in magnitude to the phase 1 response to electrical stimulation of the VMH. This, as well as the observation that pimozide blocked phase 1, suggested that dopaminergic pathways were responsible for mediating the phase 1 decrease in IBAT temperature. The peripheral mechanisms responsible for phase 1 are unknown, but a vascular component might explain the unexpected decrease in IBAT temperature seen during sustained VMH stimulation.

Adipose Tissue, Brown↗