Biomedical subjects

T F Lee

Publications and source records attributed to T F Lee.

At least 37 records · Page 2Linked to original sources

PubMed1992

Decrease in cold tolerance of aged rats caused by the enhanced endogenous adenosine activity.

During severe cold exposure, old rats (24-28 months) were less capable of maintaining their body temperature compared to young rats (3-6 months) due to lower rate of heat production. Single injection of adenosine deaminase (AD) (converts adenosine to inosine) significantly increased thermogenesis in both young and old rats. However, doubling the dose of AD was required for optimal thermogenic response in old rats. In contrast, the similar enhancements in both thermogenesis and cold tolerance were observed in both young and old rats receiving the same optimal doses of specific adenosine receptor antagonists. These results lead to the suggestion that the lower capability of aged rats to withstand cold exposure could be due to an increase in adenosine stimulation because of the decreased endogenous AD activity rather than an increase in adenosine receptor sensitivity. This notion is further supported by the finding that the AD activity in the neck muscle, a key site for shivering thermogenesis, was significantly lower in old rats as compared to their younger counterparts before and after cold exposure.

Adenosine↗

PubMed1991

Seasonal changes in methionine-enkephalin immunoreactivity in the brain of a hibernator, Spermophilus columbianus.

To identify the actual location of central endogenous opioid systems which may be involved in regulating the hibernation cycle, differences in the pattern of central methionine-enkephalin (Met-EK) immunoreactivity were compared between hibernating (body temperature, Tb = 7 degrees C) and non-hibernating (Tb = 37 degrees C) Columbian ground squirrels using the peroxidase-antiperoxidase technique. In non-hibernating animals, Met-EK-immunoreactive perikarya were observed in telencephalic (putamen, caudate nucleus, medial septum-diagonal band complex, amygdala) and diencephalic (periventricular hypothalamic nucleus, lateral hypothalamic area) regions, whereas immunoreactive fibers were found in the lateral septum, stria terminalis nucleus, various hypothalamic areas, arcuate nucleus, median eminence, thalamic intralaminar, periventricular nucleus and lateral habenular nucleus. Compared to the non-hibernating animal, a marked increase in the number of Met-EK-immunoreactive fibers was found in the lateral septal nucleus, the periventricular nucleus, the intralaminar thalamus and the paraventricular hypothalamus of hibernating ground squirrels. Since these changes in immunoreactivity were not observed in the artificially induced hypothermic ground squirrels (Tb = 7 degrees C), it is unlikely that the dissimilarity in immunoreactivity between animals from different hibernating phases is due to differences in their Tb. In combination with our previous studies, these results tend to suggest that hibernation may be brought about by an increase in endogenous opioid activity, especially in the lateral septal region.

Animals↗

PubMed1991

State-dependent variation in the inhibitory effect of [D-Ala2, D-Leu5]-enkephalin on hippocampal serotonin release in ground squirrels.

Accumulated evidence has suggested that increased endogenous opioid activities may facilitate the onset of hibernation either directly or possibly through modulation of other neurotransmitter systems. The seasonal change of [D-Ala2, D-Leu5]-enkephalin (DADLE), a delta receptor agonist, in modulating K+ (35 mM)-induced [3H]-5-hydroxytryptamine (5-HT) release from the hippocampal and hypothalamic slices of euthermic and hibernating Richardsons' ground squirrels was therefore investigated. DADLE (0.1-10 microM) had no effect on 5-HT release in the hypothalamic slices but elicited a dose-related inhibition on [3H]-5-HT release from the hippocampal slices of the euthermic ground squirrel. The inhibitory effect of DADLE was completely reversed by naloxone (10 microM), but not by tetrodotoxin (1 microM). In contrast, DADLE failed to alter the K(+)-induced 5-HT release from the hippocampal slices of the hibernating ground squirrel. This state-dependent reduction in responsiveness to an opioid is consistent with the hypothesis that enhanced endogenous opioid activity in the hibernating phase could lead to down regulation of the opioid receptors and minimize its inhibition on hippocampal serotonergic activity. A high 5-HT activity would inhibit midbrain reticular activating system indirectly through non-serotonergic fibers, which in turn facilitate the onset or maintenance of hibernation.

Animals↗

PubMed1990

Improvement of cold tolerance by selective A1 adenosine receptor antagonists in rats.

Previously we have shown that the improvement of cold tolerance by theophylline is due to antagonism at adenosine receptors rather than inhibition of phosphodiesterase. Since theophylline is a nonselective adenosine receptor antagonist for both A1 and A2 receptors, the present study investigated the adenosine receptor subtype involved in theophylline's action. Acute systemic injection of selective A1 receptor antagonists (1,3-dialkyl-8-aryl or 1,3-dialkyl-8-cyclopentyl xanthine derivatives) significantly increased both the total and maximal heat production as well as cold tolerance. In contrast, injection of a relatively selective A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (compound No. 19), failed to significantly alter the thermogenic response of the rat under cold exposure. Further, the relative effectiveness of these compounds in increasing total thermogenesis was positively correlated with their potency in blocking the A1 adenosine receptor (r = .52, p less than 0.01), but not in A2 adenosine receptor (r = .20, p less than 0.2). It is likely that the thermally beneficial effects of adenosine A1 antagonists are due to their attenuation of the inhibitory effects of endogenously released adenosine on lipolysis and glucose utilization, resulting in increased substrate mobilization and utilization for enhanced thermogenesis.

Animals↗

PubMed1990

Do adenosine antagonists improve cold tolerance by reducing hypothalamic adenosine activity in rats?

Previously we have shown that systemic injection of adenosine antagonists can significantly improve cold tolerance in both rats and humans. However, it is not clear whether systemic administration of adenosine antagonist acts peripherally or centrally at the thermoregulatory site. To resolve this, theophylline (nonselective adenosine receptor blocker), cyclopentyltheophylline (selective A1 receptor blocker) or adenosine deaminase (an enzyme which inactivates adenosine by converting it into inosine) was injected directly into preoptic anterior hypothalamus (POAH) of rats and their thermogenic responses assessed. In contrast to that observed after systemic administration, intrahypothalamic injection of either adenosine antagonists or deaminase at various doses failed to elicit any enhancement in heat production beyond that of the controls. These results suggest that the beneficial effect of systemically injected adenosine antagonists in improving cold tolerance is not the result of altering the thermoregulatory functions mediated via the POAH.

Adenosine Deaminase↗

PubMed1990

Effect of intracerebroventricular injection of neokyotorphin on the thermoregulatory responses in rats.

Intracerebroventricular injection of neokyotorphin (NKT) (0.5-2.0 micrograms) caused a dose-related increase in body temperature (Tb) of rats maintained at 28 degrees C. The change in Tb of the rat induced by the optimal dose of NKT (1 microgram) was attenuated when the rat was exposed to 18 degrees C. At both ambient temperatures, heat production was not affected but heat loss was significantly reduced at 28 degrees C in rats receiving 1 microgram NKT. Pretreatment with naloxone (5 mg/kg, IP) significantly reduced the hyperthermic effect induced by NKT (1 microgram). These results suggest that NKT can affect the prevailing thermoregulatory heat loss activities and this effect may be mediated through stimulated release of endogenous opioids.

Amino Acid Sequence↗

PubMed1990

Enhancement of maximal thermogenesis by reducing endogenous adenosine activity in the rat.

Adenosine has been shown in vitro to be a potent antilipolytic agent and an inhibitor of insulin-stimulated glucose utilization in skeletal muscle. To test whether endogenously produced adenosine (e.g., from ATP hydrolysis) shares these deleterious effects on substrate mobilization and utilization and thus limits maximum thermogenesis in vivo, adenosine deaminase (converts adenosine to inosine) was given to rats 15 min before cold exposure. Significant (P less than 0.05) increases in thermogenesis were observed under both well-fed (100 units/kg ip) and food-rationed (200 units/kg ip) states. Significant (P less than 0.05) increases in thermogenesis and cold resistance were also observed after pretreatment with selective adenosine receptor antagonists [8-cyclopentyltheophylline (1 microgram/kg ip) greater than 1,3-dipropyl-8-p-sulfophenylxanthine (1.25 mg/kg ip) greater than aminophylline (18.7 mg/kg ip)], indicating an A1-receptor-mediated effect. These results indicate that endogenously released adenosine can indeed attenuate the thermogenic capacity in severe cold and that adenosine antagonists, especially those selective for A1-receptor, are useful in improving cold resistance under varying nutritional states.

Adenosine↗

PubMed1989

Mechanisms underlying the supra-maximal thermogenesis elicited by aminophylline in rats.

Previous studies showed that acute treatment with aminophylline (AMPY) significantly elevated maximum thermogenesis and improved cold tolerance in rats and man in severe cold. However, the exact mechanism by which AMPY enhances thermogenesis was unknown. Rats receiving enprofylline (ENPRO) (1.5 and 15 mg/kg, i.p.), a selective phosphodiesterase inhibitor, failed to show enhanced thermogenesis. In contrast, treatment with a selective adenosine receptor antagonist, 8-phenyltheophylline(8-PT; 2.5 to 10 mg/kg, i.p.), significantly increased (p less than 0.05) thermogenesis and cold tolerance. However, the maximal thermogenic effect by optimal dose of 8-PT (5 mg/kg) was significantly lower than that with optimal dose of AMPY (18.7 mg/kg, i.p.); the deficit could be eradicated by combining optimal 8-PT dose with a low dose of AMPY (1.25 mg/kg), but not with ENPRO. These results indicate that the thermogenic effect of AMPY is not by inhibition of phosphodiesterase but at least partially by antagonism of adenosine receptors. It is also apparent that older mechanisms in addition to adenosine antagonism are also involved in AMPY's thermogenic action.

Adenosine↗

PubMed1988

The "hibernation induction trigger": specificity and validity of bioassay using the 13-lined ground squirrel.

Even though the existence of the blood-borne "hibernation induction trigger" has been reported in the 13-lined ground squirrel, transfusion of plasma from hibernating rodents with other hibernating species as the recipients failed to induce the occurrence of summer hibernation. In order to verify whether the response to the "trigger" substance is species specific, the present study was carried out to compare the effect of plasma from hibernating Richardson's ground squirrels on the incidence of summer hibernation in both juvenile Richardson's and adult 13-lined ground squirrels. In two series of experiments, 13-lined ground squirrels entered hibernation quite readily independent of the treatment. The rate of occurrence of hibernation ranged from 78% after sham injection to 86% after warm saline, fresh summer active plasma, and fresh hibernating plasma, respectively. There were no differences in the number of hibernation bouts and the number of days in hibernation after each treatment. In contrast, none of the juvenile Richardson's ground squirrels entered hibernation after any of the treatments up to the end of the 8-week observation period. These results not only argue against the existence of blood-borne "trigger" substance, at least in the Richardson's ground squirrel, but also caution against the use of the 13-lined ground squirrel as a standard test animal for the bioassay of the "trigger" substance.

Animals↗

PubMed1987

Seasonal difference in thermoregulatory responses to opiates in a mammalian hibernator.

Accumulated evidence suggests that increased endogenous opioid activities may facilitate the onset of hibernation. The present study investigated the change in thermoregulatory responses following ICV infusion of morphine or [D-Ala2]-Met enkephalinamide (EK) in unanesthetized, unrestrained Columbian ground squirrels (Spermophilus columbianus) during its annual hibernation cycle. In the nonhibernating phase, low doses of either morphine (less than 160 micrograms) or EK (less than 400 micrograms) elicited a dose-related hyperthermia and an increase in heat production, whereas a higher dose of opiates caused hypothermia and a decrease in metabolic rate. Naloxone (5 mg/kg, SC) pretreatment reduced or reversed both the hyper- and hypothermic responses to opiates. Lower ambient temperature (5 degrees C) enhanced the hypothermic response and attenuated the hyperthermic response. In the hibernating phase, euthermic ground squirrels exhibited a reduced responsiveness to exogenous opiates: the hyperthermic response to low dose of morphine (10 micrograms) was significantly reduced and hyperthermia, rather than hypothermia was observed at the highest dose of morphine (160 micrograms). The reduced responsiveness to opiates observed during the hibernating phase seems to suggest a reduction in opiate receptor efficacy which is in agreement with the contention that an increase in endogenous opioid activities may be incumbent with the commencement of hibernation.

Animals↗

PubMed1987

Neurotensin releases norepinephrine differentially from perfused hypothalamus of sated and fasted rat.

The central injection of neurotensin (NT) has been reported to attenuate the intake of food in the fasted animal. To determine whether endogenous norepinephrine (NE) is involved in the satiating effect of NT, the in vivo activity of NE in circumscribed sites in the hypothalamus of the unanesthetized rat was examined. Bilateral guide tubes for push-pull perfusion were implanted stereotaxically to rest permanently above one of several intended sites of perfusion, which included the paraventricular nucleus (PVN), ventromedial nucleus (VMN), and the lateral hypothalamic (LH) area. After endogenous stores of NE at a specific hypothalamic locus were radiolabeled by microinjection of 0.02-0.5 mu Ci of [3H]NE, an artificial cerebrospinal fluid was perfused at the site at a rate of 20 microliter/min over successive intervals of 5.0 min. When 0.05 or 0.1 micrograms/microliter NT (0.03-0.6 mM) was added to the perfusate, the peptide served either to enhance or reduce the local release of NE at 50% of the sites of perfusion. In these experiments, the circumscribed effect of NT on the characteristics of catecholamine efflux depended entirely on the state of hunger or satiety of the rat. That is, when NT was perfused in the fully satiated rat, NE release was augmented within the PVN or VMN; conversely, NE release was inhibited in the LH. In the animal fasted for 18-22 h, NT exerted an opposite effect on the activity of NE within the same anatomical loci in that the efflux of NE was enhanced in the LH but attenuated or unaffected in the PVN or VMN.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Enhancement of cold-stimulated thermogenesis in the corpulent rat (LA/N cp) by aminophylline.

Previous studies on obese strains of rats (e.g., Zucker and LA/N cp) have shown that they are deficient in nonshivering thermogenesis and poor in cold tolerance. Our earlier studies have established that aminophylline (AMPY; 85% theophylline-15% ethylenediamine) is effective in significantly improving cold tolerance in the lean Sprague-Dawley rat regardless of age or thermogenic capacity. The present study tested whether AMPY may be also effective in improving cold tolerance in both young (12-18 wk) and older (36-42 wk) lean and corpulent LA/N cp rats. Contrary to previous reports, however, the norepinephrine (NE)-stimulated nonshivering thermogenesis was not only present but also equal in magnitude in the corpulent rats to that of their lean controls. Further, no difference in cold tolerance was observed between the two groups regardless of age. Similarly, AMPY (18.7 mg/kg ip) significantly improved thermogenesis and cold tolerance in both lean and corpulent rats, again without any age-related difference in response. These results indicate that, despite the existence of obesity, no difference in thermogenic capacity to either NE or cold stimulation is evident in the LA/N cp rats. Thus the ontogeny of obesity in this strain may be caused by factors other than deficiency in NE- or cold-stimulated thermogenesis at the end-organ level.

Aminophylline↗

PubMed1986

CCK and other peptides modulate hypothalamic norepinephrine release in the rat: dependence on hunger or satiety.

The purpose of this investigation was to determine the functional relationship between putative satiety peptides and endogenous norepinephrine (NE) activity in the hypothalamus. Permanent guide cannulae for push-pull perfusion were implanted stereotaxically in Sprague-Dawley rats so as to rest above the medial or lateral hypothalamus (LH). Post-operatively, the animals were either satiated with food and water, both available ad lib, or fasted for 18-22 hr prior to an experiment. To perfuse a site in the LH, paraventricular (PVN) or ventromedial nucleus (VMN), a concentric 29-23 ga push-pull cannula system was lowered to a pre-determined site, in most cases after catecholamine stores had been pre-labeled with [3H]-NE. During control tests, an artificial CSF was perfused at a rate of 20-25 microliter/min for 5-8 min with a 5 min interval between each sample. The addition of cholecystokinin (CCK) in a concentration of 2.0-6.0 ng/microliter to the CSF perfused in PVN or VMN of the satiated rat enhanced the efflux of NE; however, in the fasted animal CCK often suppressed the catecholamine's release. Perfused in the LH, CCK exerted opposite effects, typically augmenting NE output when the rat was fasted but not affecting the amine's activity during the sated condition. Proglumide (1.2 micrograms/microliter) attenuated CCK's effect in releasing NE when the antagonist was perfused in the PVN of the satiated rat. Similar experiments in which neurotensin (NT) was perfused in the LH, PVN and VMN revealed virtually the same inverse effects on NE release in the fasted and satiated rat, which again were anatomically specific. Finally, insulin and 2-deoxy-D-glucose (2-DG) exerted similar state-dependent effects on the release of NE within LH and PVN. Overall, the results suggest that CCK or other neuroactive peptide could serve as a "neuromodulator" of the pre-synaptic release of NE within classical hypothalamic structures which are thought to underlie both hunger and satiety. The state-dependent nature of the peptides' activity on the noradrenergic feeding mechanism implies that these substances constitute a pivotal portion of the profile of factors which impinge functionally upon the hypothalamic neurons responsible for the feeding response and its cessation.

Animals↗

PubMed1985

Substrate preference in aminophylline-stimulated thermogenesis.

The present study investigated the suitability of different substrates on aminophylline (AMPY)-induced thermogenesis in rats during cold exposure. Feeding of distilled water 60 min prior to cold exposure in two-day fasted rats resulted in the lowest total heat production and final body temperature in both saline- and AMPY-treated groups. Feeding of 5 ml Intralipid (2 Kcal/ml), a triglyceride mixture, did not improve thermogenesis beyond the control levels. However, feeding of isocaloric substitutes of sucrose elevated significantly the total thermogenesis by 7.9% and 7.4% and final body temperature by 2.23 and 1.61 degrees C, respectively, in saline- and AMPY-treated groups. The increase in thermogenesis by sucrose is not due to its thermic effect. It is concluded that sucrose, in combination with AMPY, may be of value in improving resistance to cold.

Aminophylline↗

PubMed1985

Improving cold tolerance in elderly rats by aminophylline.

During severe cold exposure, old rats (23-26 months) were less capable in maintaining normal body temperature as compared to young rats (6-9 months) due to lower rate of heat production (HP). Single injection of optimal doses of aminophylline (AMPY; 10 and 18.7 mg/kg, i.p.), a phosphodiesterase inhibitor which enhances the intracellular cyclic AMP concentration, significantly increased the rate of HP in old rats to levels beyond the control values observed in young rats. Consequently, cold tolerance of the old rats was significantly improved. This AMPY-improved cold tolerance is apparently not due to increased non-shivering thermogenesis (NST) since AMPY failed to enhance norepinephrine-stimulated NST in the old rats. It is likely that AMPY increased substrate mobilization and/or conversion, thereby circumventing the limiting role of substrate availability for shivering thermogenesis. Thus, the age-dependent decrease in cold tolerance may be due to a reduced capacity for substrate mobilization when challenged by cold.

Aging↗

PubMed1985

Dopamine and thermoregulation: an evaluation with special reference to dopaminergic pathways.

The complex role of dopamine (DA) in the diencephalic mechanisms involved in the control of body temperature is reviewed and evaluated. In the context of the monoamine theory of thermoregulation, catecholaminergic synapses in the anterior hypothalamic pre-optic area, are proposed mediate the pathways in the brain-stem which subserve heat dissipation. Within this theoretical framework, hypothalamic DA is considered to underlie a portion of the functional component of the heat loss system. This deduction is based on pharmacological studies in which both the catecholamine and receptor antagonists have been infused directly into the hypothalamus. In view of the action of DA applied to the substantia nigra and other subcortical structures, the unique anatomical circuitry of the central dopaminergic projections has also been analyzed in terms of specific connections within critical morphological regions related to thermal functions. In particular, the nigro-striatal pathway could be involved in the mediation of one or more of the different aspects of the thermoregulatory system integrating both autonomic and behavioral responses. Finally, an anatomical schema which portrays the suggested mechanisms of DA activity is presented.

Animals↗

PubMed1985

Effect of intracerebroventricular vasopressin on body temperature and endotoxin fever of macaque monkey.

In the adult monkey (Macaca fasicularis) acclimated to a primate restraint chair, intracerebroventricular (ICV) cannulas were stereotaxically implanted bilaterally in the lateral cerebral ventricle. During an experiment, colonic and skin temperatures were continuously recorded, and in selected cases heart and respiratory rates as well as O2 consumption were similarly monitored. Arginine vasopressin (AVP) was infused ICV in a volume of 500 microliter in one of six doses ranging from 16 to 4,240 ng. The results showed that AVP in all doses infused failed to alter the resting core and skin temperatures of the monkey or other recorded physiological responses. After a fever was produced in the monkey by 1/10-1/100 dilution of Escherichia coli endotoxin infused ICV, AVP at doses of 16-260 ng did not augment the febrile response. Further, AVP infused in the same range of doses caused only a negligible and inconsistent antipyretic action; i.e., the 65-ng dose of AVP lowered the mean core temperature of the febrile monkey by only 0.5 degrees C. This was in marked contrast to the antipyretic effect of dipyrone administered systemically. In addition, no reproducible changes occurred in respiratory, heart, or metabolic rates after ICV infusion of AVP. These results indicate that AVP does not affect the normal thermoregulatory function of this species of monkey and, in contrast to other species, a febrile response is neither enhanced nor antagonized in the monkey by a central action of AVP. Although AVP thus does not appear to be an endogenous antipyretic in the monkey, anatomic investigations will be required to substantiate this conclusion in the subhuman primate.

Animals↗

PubMed1984

Neurotensin perfusion of rat hypothalamus: dissociation of dopamine release from body temperature change.

To determine whether endogenous dopamine is involved in the impairment of body temperature induced by neurotensin, the local activity of [14C]dopamine in the hypothalamus of the unanesthetized rat was examined. A push-pull guide tube was implanted permanently above an intended site of perfusion within the anterior hypothalamic, pre-optic area or other region of the diencephalon. After the endogenous stores of dopamine at a specific site were labelled by microinjection of 0.02-0.05 muCi of [14C]dopamine, an artificial cerebrospinal fluid was perfused at the site at a rate of 20 microliter/min and at successive 5 min intervals. Perfusion of neurotensin in concentrations of 0.05 or 0.1 microgram/microliter in the dorsomedial hypothalamus, lateral hypothalamus, arcuate nucleus or diagonal band of Broca evoked a calcium-dependent efflux of [14C]dopamine. The release of dopamine induced by neurotensin was functionally specific since it was: (1) not mimicked by the relatively inactive neurotensin analogue, [D-Arg9]neurotensin; (2) dependent on the morphological locus of the push-pull perfusion; and (3) not accompanied by an efflux of [3H]norepinephrine when the site was double-labelled. Although neurotensin perfused in the anterior hypothalamic, pre-optic area caused a consistent decline in temperature, in most cases the temperature change did not correlate with an enhanced release of dopamine. Moreover, the release of dopamine, but not the temperature change, was abolished when neurotensin was perfused in a calcium-free medium. These results show that it is unlikely that the thermolytic action of neurotensin, at least within the hypothalamus, is mediated by the presynaptic release of dopamine.

Animals↗