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Biomedical subjects

B Cannon

Publications and source records attributed to B Cannon.

At least 55 records · Page 3Linked to original sources
PubMed1996

Down-regulation of beta3 adrenoreceptor gene expression in brown fat cells is transient and recovery is dependent upon a short-lived protein factor.

The regulation of the expression of the beta3 adrenoreceptor gene was examined in the brown adipose tissue of intact mice and in murine brown fat primary cell cultures. Both in vivo and in vitro, high levels of beta3 receptor mRNA were observed. Acute cold exposure of mice resulted in a marked and rapid down-regulation of beta3 gene expression; this down-regulation was, however, transient. Similarly, in brown fat cell cultures, norepinephrine addition led to down-regulation of beta3 gene expression, with a lag phase of 30 min and with an apparent half-life of beta3 mRNA of approximately 30 min. This down-regulation was stimulated via the beta3 receptors themselves and mediated via cAMP; the apparent affinity of norepinephrine was extremely high (<1 nM). The degradation rate after actinomycin was identical to that after norepinephrine and was not affected by the presence of norepinephrine; thus, the down-regulation was due to cessation of transcription but not to an increased rate of degradation. Notably, inhibition of protein synthesis by cycloheximide also led to down-regulation. The norepinephrine-induced down-regulation was transient; spontaneous recovery occurred after approximately 18 h and was not due to depletion of adrenergic agent. Recovery did not occur in the presence of cycloheximide. After recovery, the cells showed a functional desensitization of the down-regulation process itself (EC50 now approximately 10 nM). It is concluded that a down-regulated state cannot explain the functional desensitization of beta3 adrenergic responsiveness observed in brown fat cells isolated from cold-acclimated animals (i.e. physiologically chronically adrenergically stimulated brown fat cells); since the beta3 receptor is not subject to desensitization via phosphorylation processes, no satisfactory explanation for the functional desensitization exists as yet. A model is presented for the down-regulation/recovery process, involving the participation of a phosphorylatable short-lived transcription factor.

Adipose Tissue, Brown↗
PubMed1996

Cold-induced reduction in Gi alpha proteins in brown adipose tissue. Effects on the cellular hypersensitization to noradrenaline caused by pertussis-toxin treatment.

The significance of Gi proteins for the physiological desensitization phenomena observed in brown-fat cells from cold-acclimated hamsters was investigated. For this purpose, pertussis toxin (the inhibitor of Gi function) was injected into control and cold-acclimated hamsters. After 3 days the thermogenic response to noradrenaline injection was monitored in the intact animals. It was found that the pertussis-toxin pretreatment did not affect the thermogenic response to noradrenaline. Nonetheless, the pertussis toxin pretreatment had a dramatic effect on the noradrenaline-sensitivity of isolated brown-fat cells (measured the following day as the respiratory response): a 250-fold-increased sensitivity to noradrenaline was observed in cells from control animals that had been pertussis-toxin pretreated. However, only a 20-fold increase was observed in cells from cold-acclimated hamsters, implying a lower complement of the Gi system in these cells. Therefore the content of Gi proteins was determined by quantitative immunoblotting of purified plasma-membrane proteins. Cold acclimation resulted in a nearly 50% reduction in the content of Gi 1 alpha and Gi 2 alpha, as well as of the beta-subunit, both when expressed on a protein basis and when related to the content of forskolin-stimulated adenylyl cyclase; when expressed per unit of [3H]ouabain-binding (NA+/K+-ATPase), the reduction was even higher. In view of the magnitude of the pertussis-toxin effect, it was concluded that Gi proteins must play a substantial role in the regulation of the response of brown-fat cells to noradrenaline. As the capacity of the Gi pathway is reduced rather than augmented during cold acclimation, Gi activity cannot be responsible for the desensitization to noradrenaline observed in cells from cold-acclimated animals. However, the reduced Gi content may explain the earlier observed desensitization to adenosine that occurs after acclimation to cold.

Acclimatization↗
PubMed1996

Postnatal selective suppression of lipoprotein lipase gene expression in brown adipose tissue (relative to the expression of the gene for the uncoupling protein) is not due to adrenergic insensitivity: a possible specific inhibitory effect of colostrum.

The levels of mRNA coding for the uncoupling protein (UCP) and for lipoprotein lipase (LPL) were monitored in the brown adipose tissue of newborn rat pups. At 5 h after birth, the mRNA levels of UCP and LPL were high in pups exposed singly to 28 degrees C and low in pups kept singly at thermoneutrality (36 degrees C); in pups staying with the dam, the UCP mRNA levels were intermediate. However, the LPL mRNA levels were lower in pups staying with the dam than in pups at 36 degrees C, implying that factors additional to environmental temperature influenced LPL gene expression. Injection of noradrenaline into pups at thermoneutrality (36 degrees C) led to increases in UCP and LPL gene expression, but noradrenaline injections had no further effect in cold-exposed pups. The adrenergic effects were mediated via beta-adrenergic receptors. The cold-induced increases in both UCP and LPL gene expression were abolished by the beta-adrenergic antagonist propranolol. Thus differences in adrenergic responsiveness could not explain the differential expression of the UCP and LPL genes observed in pups staying with the dam. The presence of a physiological suppressor was examined by feeding single pups at 28 degrees C with different foods: nothing, water, Intralipid, cow's milk, rat milk and rat colostrum. None of these agents led to suppression of UCP gene expression, but colostrum led to a selective suppression of LPL gene expression. It was concluded that the genes for UCP and LPL were responsive to adrenergic stimuli immediately after birth, and it is suggested that a component of rat colostrum can selectively suppress LPL gene expression.

Actins↗
PubMed1996

Stimulation of nonshivering thermogenesis in the Syrian hamster by norepinephrine and beta-selective adrenergic agents: a phenomenon of refractoriness.

The ability of different adrenergic agents to stimulate nonshivering thermogenesis in Syrian hamsters was investigated. The hamsters were cold-acclimated to 6 degrees C and their thermogenic response was investigated in an open-circuit system at 24 degrees C. Both norepinephrine and the beta 3-specific adrenergic agonist CGP-12177 induced a high rate of nonshivering thermogenesis. However, neither CGP-12177 nor other beta 3-selective agonists (BRL-37344, ICI-D7114) could induce nonshivering thermogenesis fully to the extent induced by norepinephrine. It was further observed that an apparent "thermogenic refractoriness" was induced by certain adrenergic agents (isoprenaline, CGP-12177) but not by others (norepinephrine, BRL-37344, ICI-D7114). It is discussed whether the refractoriness could be secondary to effects of these agents on the vascular system. It is pointed out that the thermogenic response to adrenergic stimulation observed in the intact animal does not always fully correspond to what would be predicted from corresponding studies with isolated brown-fat cells.

Acclimatization↗
PubMed1996

Clinical laboratory tests: application to daily practice.

Along with physical examination and medical history, clinical laboratory tests are an essential evaluative tool of health professionals. Pharmacists have a key role in selecting appropriate laboratory tests for TDM, interpreting tests to determine whether a drug is producing its desired therapeutic effect, and avoiding adverse drug effects. Prudence dictates that pharmacists should recommend that a laboratory test be done only if the results may lead to some action such as a dosage reduction, discontinuation of a drug, or ordering of additional tests to confirm the presence of an adverse effect. In these cost-conscious times, panels of laboratory tests that include multiple assays (Table 5) should be recommended only when it is less expensive to order the panel than to order individual tests, or when multiple tests are needed to evaluate the patient's situation. Pharmacists should be familiar with useful references to help interpret and apply lab test results to particular patient situations, so that they can make appropriate recommendations for altering drug therapy. Pharmacists with an appreciation of the role of clinical laboratory testing in patient care can perform a valuable service for their patients and other health professionals.

Clinical Laboratory Techniques↗
PubMed1996

Signal transduction in brown adipose tissue recruitment: noradrenaline and beyond.

The classical effect of noradrenaline on brown adipose tissue is stimulation of heat production. However, it is likely that noradrenaline is also the major regulator of proliferation and differentiation. The adrenergic receptors involved include at least beta 1, beta 3, alpha 2 and alpha 1. Heat production is mainly stimulated via beta 3 receptors and cAMP. Cell proliferation is mainly stimulated via beta 1 receptors and cAMP. Cell differentiation is also adrenergically promoted; at least the expression of the gene for the tissue-specific uncoupling protein thermogenin is controlled via beta 3 receptors and cAMP. There is a switch in beta-receptor endowment between young (beta 1) and mature (beta 3) cells. The expression of several transcription factors is also under adrenergic control: c-Fos gene expression depends synergistically on beta- and alpha 1-stimulation mediated via cAMP and [Ca2+]i increases. C/EBP beta gene expression is regulated only via beta-receptors, but the expression of the C/EBP alpha gene shows a switch during differentiation: in young cells, the expression is represented through both beta- and alpha 1-receptors; in mature cells, the expression is stimulated via b-receptors. It is likely that noradrenaline exerts its proliferation- and differentiation-promoting action through alterations in the expression of these or other transcription factors.

Adipose Tissue, Brown↗
PubMed1995

The expression of subunit c correlates with and thus may limit the biosynthesis of the mitochondrial F0F1-ATPase in brown adipose tissue.

A low content of mitochondrial ATPase in brown adipose tissue (BAT) has previously been found to contrast with high levels of the transcripts of the beta-subunit of the F1 part of the ATPase and of the transcripts of the mitochondrial encoded subunits (Houstĕk, J., Tvrdík, P., Pavelka, S., and Baudysová, M. (1991) FEBS Lett. 294, 191-194). To delineate which subunit limits the synthesis of the ATPase complex, we have studied the expression of the nuclear genes encoding subunits alpha, beta, and gamma of the catalytic F1 part and the b, c, d, and OSCP subunits of the F0 part of the ATPase. In comparison with other tissues of mice, high levels of transcripts of alpha-F1, beta-F1, gamma-F1, b-F0, d-Fo, and OSCP were found in BAT. The only genes expressed at a low level in BAT were those of the c-F0 subunit. The levels of c-F0 transcripts were 4-70-fold lower in BAT than in other tissues. An analogous expression pattern of the ATPase genes was found in BAT of adult rat and hamster. In BAT of newborn lamb, which, in contrast to other mammals, has a high content of mitochondrial ATPase, correspondingly high levels of c-F0 mRNA were found Expression of the c-F0 genes also correlated well with the ontogenic development of BAT in the hamster, being high during the first postnatal week when mitochondria are nonthermogenic and contain a relatively high amount of ATPase, but low on subsequent days when ATPase content decreases, as the thermogenic function develops. It is suggested that expression of the c-F0 genes and subsequent synthesis of the hydrophobic subunit c of the membrane-intrinsic F0 part of the enzyme may control the biosynthesis of the ATPase complex in BAT. An analogous regulatory role of the c-F0 subunit could be postulated in other tissues.

Adipose Tissue↗
PubMed1995

Halothane selectively inhibits nonshivering thermogenesis. Possible implications for thermoregulation during anesthesia of infants.

BACKGROUND: During halothane anesthesia, infants fail to increase oxygen consumption in response to a cold stimulus in the form of an increase in temperature gradient between body and environment. Based on recent observations with isolated brown-fat cells, it seemed feasible that this inability to respond could be due to an inhibition of nonshivering thermogenesis during halothane anesthesia. METHODS: The rate of oxygen consumption was measured in cold-acclimated hamsters and rats. The rate evoked by norepinephrine injection in hamsters at an environmental temperature of approximately 24 degrees C was used as a measure of the capacity for nonshivering thermogenesis. Anesthesia was induced by 3% halothane and maintained by 1.5% halothane. One experimental series with spontaneously breathing hamsters and a second control series with spontaneously breathing rats and with rats whose lungs were mechanically ventilated were conducted. RESULTS: Norepinephrine injection led to a fourfold increase in the rate of oxygen consumption in control hamsters; after this response had subsided, a second injection led to a similar effect. Halothane anesthesia caused an approximately 20% decrease in resting metabolic rate (P < 0.05) and a 70% inhibition of the thermogenic response to norepinephrine (P < 0.001). The halothane concentration yielding half-maximal inhibitory effect was estimated to be less than 1.0%. After the animals had recovered from halothane anesthesia, a completely restored thermogenic response to norepinephrine was observed. The inhibitory effect of halothane also was observed in hamsters maintained at normothermia and was therefore not secondary to the slight hypothermia that otherwise developed during anesthesia. In a series of control experiments, it was confirmed that rats also showed large thermogenic responses to norepinephrine injections, and it was found that, in spontaneously breathing halothane-anesthetized rats, the thermogenic response to norepinephrine was also much inhibited. Further, in halothane-anesthetized rats whose lungs were mechanically ventilated, and where blood gases were kept at virtually normal levels, the thermogenic response to norepinephrine was found to be similarly markedly inhibited. CONCLUSIONS: A much diminished or abolished thermogenic response to injected norepinephrine was demonstrated in halothane-anesthetized animals. This implies that there would be a diminished ability to elicit nonshivering thermogenesis even when this process is physiologically induced. Such a diminished ability could in part explain the susceptibility of neonates and infants to hypothermia during halothane anesthesia.

Adipose Tissue, Brown↗
PubMed1995

Polyunsaturated fatty acids recruit brown adipose tissue: increased UCP content and NST capacity.

To examine the effect of polyunsaturated fatty acids (PUFA) on brown adipose tissue recruitment and on the capacity for nonshivering thermogenesis (NST), mice were fed a diet with a standard fat content (9%) and a normal PUFA content (1.6%) (controls) or a high-PUFA content (4.3%) for 2-3 wk. The resting metabolic rate was somewhat lower in the high-PUFA group, probably due to a lower physical activity whereas the capacity for NST (estimated as the metabolic response to a norepinephrine injection) was higher in the high-PUFA group. There was no significant effect on brown adipose tissue wet weight, protein content, or cytochrome-c oxidase content, but the amount of the uncoupling protein thermogenin (UCP), measured immunologically, was significantly increased in the high-PUFA mice (totally by 41%). It was concluded that short-term feeding of a high-PUFA diet may recruit brown adipose tissue thermogenic capacity; it was speculated that earlier-reported recruiting effects of high-fat diets may not be due solely to the high total fat content of the diet but perhaps also to a specific recruiting property of the high-PUFA diets generally used in this type of investigation.

Adipose Tissue, Brown↗
PubMed1995

Cold acclimation-recruited nonshivering thermogenesis: the Syrian hamster is not an exception.

Biochemical evidence from in vitro studies of brown adipose tissue in Syrian hamsters indicates a significant degree of recruitment of the tissue as an effect of cold acclimation. However, earlier in vivo studies indicate a lack of recruitment of nonshivering thermogenesis in the intact animal as a result of cold acclimation. Because of this apparent discrepancy, the occurrence of cold acclimation-recruited nonshivering thermogenesis in hamsters was investigated. Hamsters were cold acclimated to 6 degrees C or remained at 24 degrees C (controls), and their thermogenic response was investigated in an open-circuit system at 24 degrees C. Cold acclimation resulted in a small increase in resting metabolic rate and a major increase in the thermogenic response to norepinephrine (61% increase over resting metabolic rate in controls and 156% increase in cold-acclimated animals). The absolute beta 3-specific adrenergic agonist CGP-12177 also induced a high rate of nonshivering thermogenesis, which was similarly recruited. It was concluded that, concerning the relative effect of recruitment on the capacity for nonshivering thermogenesis, the intact hamsters responded as would be predicted from in vitro experiments. Thus the hamster does not seem to constitute an exception to the general patterns described for other rodents concerning recruitment of nonshivering thermogenesis due to cold acclimation.

Acclimatization↗
PubMed1995

Psychological screening of impotence with Finney's MMPI-derived Impotence Scale.

Three groups of patients in treatment were assessed for impotence, using MMPI-derived Impotence Scale. Group I were 46 patients who had been screened and scheduled for a penile prosthesis when the impotence resulted from known organic causes (biogenic). Group II were 198 patients in a sexual dysfunction clinic, for whom biogenic causes had been ruled out (psychogenic). Group III were 51 substance abusers in drug rehabilitation. While scores on the Impotence Scale did not distinguish between the biogenic and psychogenic groups, the scores were almost three times higher than average scores among subjects in the standardization sample. MMPI-derived Impotence Scale scores were similarly elevated among the substance abusers. Results suggest that the Impotence Scale may serve as a useful screening tool to alert clinicians to the possibility of erectile dysfunction for which further clinical evaluation would be required.

Adult↗
PubMed1995

Chart for preparation of dilutions of alpha-adrenergic agonists for intracavernous use in treatment of priapism.

Treatment of priapism with intracavernous alpha-adrenergic agonist vasoconstrictor agents is well accepted, particularly for patients with priapism secondary to intracavernous injections of papaverine, phentolamine and/or prostaglandin E1. Although many alpha-adrenergic agonists are commercially available, phenylephrine is preferred because it has potent and selective alpha 1-adrenergic stimulatory properties, which can decrease arteriolar flow to the cavernous sinusoids, and no beta 1-stimulatory effect, which could cause arrhythmias and angina in susceptible patients. Before intracavernous injection or irrigation an alpha-adrenergic agonist must be diluted. However, no readily available reference source lists this information. Therefore, we prepared a chart for extemporaneous preparation of dilutions of alpha-adrenergic agonists for intermittent injection or irrigation.

Adrenergic alpha-Agonists↗
PubMed1995

Norepinephrine as a morphogen?: its unique interaction with brown adipose tissue.

Norepinephrine is normally considered a neurotransmitter mediating acute metabolic effects in target cells. However, analysis of the regulation of the recruitment process in brown adipose tissue has indicated that norepinephrine may interact with this tissue in such a way that it could be considered a morphogen for this tissue. Besides stimulating the acute thermogenic processes, norepinephrine can induce the expression of tissue-specific proteins such as the uncoupling protein, induce expression of non-tissue specific proteins necessary of the thermogenic processes (e.g. lipoprotein lipase) and repress the expression of non-essential proteins (e.g. subunit c of the ATP-synthase). Upon chronic adrenergic stimulation, the general differentiation state of the tissue is advanced, indicating that the expression of factors with a more general effect on brown adipocyte differentiation is also under adrenergic control. It may even be discussed that norepinephrine may be involved early in the embryonal determination process directing cell clones into this line. The molecular basis for these effects of norepinephrine are only poorly known at present, but adrenergic effects on the expression level of many transcription factors, such as C/EBPalpha, C/EBPbeta, and PPARgamma 2, have been noted. These collective recruitment effects of norepinephrine are well suited to allow the tissue to grow or atrophy in response to the physiological needs of the organism.

Adipose Tissue↗
PubMed1994

Choline+ is a low-affinity ligand for alpha 1-adrenoceptors.

The effect of choline+, a commonly used Na+ substitute, on ligand binding to alpha 1-adrenoceptors was investigated. It was found that replacement of 25% of the Na+ in a Krebs-Ringer bicarbonate buffer with choline+ led to a 3-fold decrease in the apparent affinity of [3H]prazosin for its binding site (i.e. the alpha 1-receptor) in a membrane preparation from brown adipose tissue, while no decrease in the total number of binding sites was observed. Similar effects were seen in membrane preparations from liver and brain. In competition experiments, it was found that choline+ could inhibit [3H]prazosin binding; from the inhibition curve, an affinity (Ki) of 31 mM choline+ for the [3H]prazosin-binding site could be calculated. In fully choline(+)-substituted buffers, where the level of [3H]prazosin binding was substantially reduced, both phentolamine and norepinephrine could still compete with [3H]prazosin for its binding site, with virtually unaltered affinity; thus choline+ did not substantially affect the characteristics of those receptors to which it did not bind. Choline+ did not affect the binding characteristics of the beta 1/beta 2 radioligand [3H]CGP-12177; thus, the effect on alpha 1-receptors was not due to general, unspecific effects on the membrane preparations. It is concluded that choline+ possesses characteristics similar to those of a competitive ligand for the alpha 1-adrenoceptor; it has a low affinity but the competitive type of interaction of choline may nonetheless under experimental conditions interfere with agonist interaction with the alpha 1-receptor.

Adipose Tissue, Brown↗