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Biomedical subjects

M J Stock

Publications and source records attributed to M J Stock.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1993

Keeping warm.

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Complementary Therapies↗
PubMed1993

Effects of beta-adrenoceptor agonists and antagonists on thermoregulation in the cold in lean and obese Zucker rats.

This experiment examines whether the thermoregulatory ability of obese Zucker rats is comparable to that of lean rats following treatment with beta-adrenoceptor agonists and antagonists in a cold (-8 degrees C) environment. Half-maximal doses of the nonselective beta-adrenoceptor agonist isoproterenol (ISO) produced net thermolytic (heat loss) effects in both obese and lean rats in an operant lever pressing for radiant heat task. ISO increased the demand for heat, but posttest colonic temperature (Tc) decreased. A low dose of propranolol (100 micrograms/kg) normalized thermoregulatory behavior, Tc, and thermal balance when coadministered with ISO. Activation of thermogenesis with the selective beta 3-agonist BRL 35135 (BRL) reduced heat influx by both obese and lean rats at doses between 2 and 10 micrograms/kg, but no dose-response effects were evident within this range. Posttest Tc and thermal balance indicated no thermolytic effects. No evidence was found for a beta 2-component in the BRL response when a supramaximal dose (40 micrograms/kg) was tested with the selective beta 2-antagonist ICI 118551 (1 mg/kg). These data show that, despite a higher baseline demand for heat, the obese Zucker rat responds to the thermogenic effects of BRL and the thermolytic effects of ISO as does the lean rat.

Adrenergic beta-2 Receptor Antagonists↗
PubMed1993

Thermoregulatory responses to beta-adrenergic agonists at low ambient temperatures in the rat.

Dose-response effects on heat production (HP) and dry heat loss (DHL) following injection with the non-selective (beta 1/beta 2) adrenergic agonist isoprenaline (ISO) and the atypical B3 agonist BRL 35135 (BRL) were established at an ambient temperature of 25 degrees C in rats. Subsequently, the effects of HP and DHL of a maximal thermogenic dose of ISO (75 micrograms/kg) and a supramaximal dose of BRL (40 micrograms/kg) were tested at ambient temperatures of 5, 10 and 15 degrees C. In terms of heat production, BRL was no different from saline at 5 degrees C, but its thermogenic activity became increasingly evident as ambient temperature increased. For ISO, HP was lower than, or no different from, saline at 5 and 10 degrees C, respectively, but DHL exceeded HP at both temperatures, and colonic temperature fell significantly; ISO and BRL responses were similar at 15 degrees C. ISO was also capable of producing a decrease in HP at 10 degrees C if the rats were shaven. Substitution for endogenous, sympathetically mediated thermogenesis would explain the attenuation of the BRL and ISO effects at cool ambient temperatures, whereas the hypothermic effects of ISO in the cold appeared to be due to an inappropriate increase in DHL, which was exacerbated at 5 degrees C by a reduction in HP below saline values. The increase in DHL was consistent with beta 2-mediated effects of ISO on peripheral blood flow, but the mechanism responsible for the reduction in HP in the cold is unknown, although reduced vascular thermogenesis has been offered as a putative explanation.

Adipose Tissue, Brown↗
PubMed1993

Thermoregulatory effects of beta adrenoceptors: effects of selective agonists and the interaction of antagonists with isoproterenol and BRL-35135 in the cold.

Dose-dependent effects of the selective beta 1 adrenergic antagonist atenolol and the beta 2 antagonist erythro-dl-1-(7-methylinden-4-yloxy)-3-isopropylamino-2-ol were tested on the thermoregulatory responses elicited by half-maximal thermogenic doses of the nonselective beta agonist isoproterenol (ISO) in a cold environment. ISO alone increased operant responding for exogenous heat but decreased body temperature and increased net heat loss. These effects of ISO were blocked by erythro-dl-1-(7-methylinden-4-yloxy)3-isopropylamino-2-ol in a dose-dependent manner, whereas atenolol at the highest dose tested (2 mg/kg) exacerbated the effects of ISO. The beta 3 agonist, (R*,R*-(+/-)-methyl 4-[2-[2-hydroxy-2-(3-chlorophenyl)ethylamino]propylphenoxyacetate hydrobromide, reduced operant responding for heat and net heat loss in the cold; these effects were sustained in the presence of both beta 1 and beta 2 antagonists. The beta 2 adrenoceptor agonist, fenoterol, produced a dose-dependent increase in operant behavior but colonic temperature fell and thermal balance reflected the characteristic effects of a thermolytic agent. The beta 1 agonist, prenalterol, had no apparent effect on thermoregulatory behavior, colonic temperature or thermal balance but it blocked the thermolytic effects of fenoterol when both agonists were coadministered. Fenoterol had no significant effect on metabolic rate or colonic temperature when tested in a warm ambient temperature of 23 degrees C but it decreased colonic temperature without a significant effect on metabolic rate at an ambient temperature of 5 degrees C, suggesting an effect on heat loss mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1992

Evidence for an atypical, or beta 3-adrenoceptor in ferret tracheal epithelium.

1. A preparation of the ferret trachea in vitro was used to examine the effects of three selective beta-adrenoceptor agonists on lysozyme secretion from submucosal gland serous cells and epithelial albumin transport into tracheal mucus following sustained, submaximal stimulation of mucus production with methacholine (20 microM). 2. Prenalterol, salbutamol and BRL 37344 all enhanced methacholine-induced albumin output. BRL 37344 was 10,000 times more potent than salbutamol, and salbutamol was slightly more potent than prenalterol. The concentrations required to increase albumin output by 100% (EC100%) were 1.4 nM, 0.7 mM and approximately 1.0 mM for BRL 37344, salbutamol and prenalterol, respectively. All three agonists inhibited methacholine-induced lysozyme output, with salbutamol being 60 times more potent than BRL 37344, and BRL 37344 being approximately 100 times more potent than prenalterol. 3. The selective beta 2-adrenoceptor antagonist, ICI 118551, inhibited the increase in albumin output produced by BRL 37344, but much more potent at inhibiting the response to salbutamol; the pA2 for ICI 118551 was 5.55 and 7.18 (P less than 0.001) when the agonist was BRL 37344 and salbutamol, respectively. ICI 118551 also attenuated the inhibition of lysozyme output produced by the two agonists, but was 10-30 times more potent at inhibiting this response than the albumin response to BRL 37344 and salbutamol. 4. The greater potency (4-5 orders of magnitude) of BRL 37344, compared to the beta 1- (prenalterol) and beta 2- (salbutamol) adrenoceptor selective agonists, in stimulating methacholine-induced albumin transport suggests that tracheal epithelium possess an atypical, or beta 3-adrenoceptor similar to that previously reported for adipocytes and gastrointestinal smooth muscle. The weak antagonism of the response to BRL 37344 by ICI 118551 would also be consistent with an atypical adrenoceptor mediating the albumin transport response. Inhibition of methacholine-induced serous cell lysozyme output would appear to be mediated predominantly by beta2-adrenoceptors.5. In view of the possible beneficial protective effects of albumin in airway surface liquid, selective beta3-agonists like BRL 37344 might have potential value in the prevention and/or treatment of inflammatory airway disease.

Adrenergic beta-Agonists↗
PubMed1992

Potentiation of thermoregulatory responses to isoproterenol by beta-adrenergic antagonists.

The thermoregulatory effects of isothermogenic doses of isoproterenol (Iso) and a novel beta-agonist (BRL 35135) were tested in rats at 22 degrees C and in rats trained to bar press for radiant heat at -8 degrees C. BRL 35135 produced hyperthermia at 22 degrees C and reduced operant responding for heat at -8 degrees C, whereas Iso reduced body temperature and increased operant responding. In both situations, the negative effects of Iso on thermal balance were abolished by propranolol at doses that did not inhibit heat production. In anesthetized rats, propranolol potentiated the Iso-induced rise in brown adipose tissue and colonic temperature. The potentiation was more marked with the beta 2-selective antagonist ICI 118,551, whereas treatment with the beta 1-selective antagonist atenolol resulted in a profound Iso-induced reduction in temperature. The two selective antagonists also produced divergent responses in operant behavior in Iso-treated rats at -8 degrees C. These experiments demonstrate the extent to which responses to a nonselective agonist can be manipulated using appropriately low doses of selective antagonists and indicate that the effects of Iso on thermal balance are due to its beta 2 activity.

Adrenergic beta-Agonists↗
PubMed1991

Effects of central injection of glucose on thermogenesis in normal, VMH-lesioned and genetically obese rats.

Intra-cerebroventricular (i.c.v.) injection of glucose (0.1-1.0 mumol) caused dose-dependent increases in resting oxygen consumption (Vo2) of conscious rats (maximum increase of 15.4 +/- 2% at 0.5 mumol). These effects were significantly attenuated by peripheral (i.p.) pretreatment with the beta-adrenoceptor propranolol, indicating the importance of the sympathetic nervous system (SNS) in the response. Plasma glucose concentrations were elevated (11%) 30 min after central injection of glucose, but intravenous glucose (0.5 mumol) did not affect resting Vo2. Animals which had been fasted for 12 h prior to Vo2 measurement exhibited reduced basal Vo2 values, but the nutritional state of the animal did not affect the metabolic response to central injections of glucose (0.5 mumol). Rats exhibiting genetic (fa/fa Zucker rats) and hypothalamic (VMH-lesioned) obesity showed similar thermogenic responses to centrally administered glucose, to their lean counterparts. These data suggest a dual action of central glucose in the regulation of energy balance, involving stimulation of energy expenditure in addition to its reported inhibition of energy intake. The defective diet-induced thermogenesis associated with VMH and genetic obesities does not appear to result from an inability to respond to changes in intracerebroventricular glucose concentrations.

Animals↗
PubMed1991

Effect of conventional (mixed beta 1/beta 2) and novel (beta 3) adrenergic agonists on thermoregulatory behavior.

The effects of submaximal and maximal thermogenic doses of isoproterenol (ISO) on operant thermoregulatory responses in a cold (-8 degrees C) environment were tested in lean (+/?) Zucker rats trained to barpress for radiant heat. Contrary to expectations, ISO rats pressed for twice as much exogenous heat as controls, but showed a smaller rise in colonic temperature. Conversely, a beta 3-selective adrenergic agonist (RO40-2148) decreased the requirement for exogenous heat and produced larger rises in colonic temperature. RO40-2148 and another beta 3-agonist (ICI D7114) produced similar responses in obese (fa/fa) Zucker rats, but tests with ISO were terminated because it caused profound, and lethal hypothermia. The hypothermic effects of ISO on colonic temperature were also observed in Sprague-Dawley rats at room temperature (22 degrees C), whereas RO40-2148 produced hyperthermia. These results provide behavioral evidence for the high thermogenic selectivity of these novel adrenergic agonists and support the existence of an atypical beta 3-adrenoceptor. The hypothermic effects of ISO are presumed to be due to actions on beta 1- and/or beta 2-adrenoceptors.

Adrenergic beta-Agonists↗