Effect of beta-adrenergic drugs on LH, FSH, and growth hormone (GH) secretion in conscious, ovariectomized rats

The effects of third ventricular (3V) injection of the beta-adrenergic antagonist, propranolol (PROPR), a selective beta 1-antagonist, metoprolol (MET), a selective beta 2-antagonist, IPS 339, and a beta-adrenergic agonist (-) isoproterenol (ISOPR), on plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), and growth hormone (GH) were studied in conscious, ovariectomized (OVX) rats. Samples were removed from unrestrained rats which had been previously implanted with atrial and 3V cannulae, and plasma hormone levels were determined by radioimmunoassay (RIA). Intraventricular injection of PROPR (30 micrograms), MET (40 micrograms), or IPS 339 (20 micrograms) induced a gradual elevation in plasma GH concentrations, whereas ISOPR (30 micrograms) reduced plasma GH. ISOPR (30 micrograms) brought about a decrease in plasma LH concentrations, but PROPR, MET and IPS 339 had no effect on LH levels. PROPR (30 micrograms) increased plasma FSH concentrations, but there was no significant effect of MET, IPS 339 or ISOPR on FSH secretion. The results indicate that the beta-adrenergic system can inhibit the release of GH, LH, and FSH. This system appears to have a tonic inhibitory effect on GH and FSH but not LH release in the OVX rat.     

The Therapeutic Effects and Mechanisms of Salidroside on Cardiovascular and Metabolic Diseases: An Updated Review

The increasing incidence of metabolic and cardiovascular diseases has severely affected global human health and life safety. In recent years, some effective drugs with remarkable curative effects and few side effects found in natural compounds have attracted attention. Salidroside (SAL), a phenylpropane glycoside, is the main active ingredient of the plateau plant Rhodiola. So far, many animal experiments proved that SAL has good biological activity against some metabolic and cardiovascular diseases. However, most of these reports are scattered. This review systematically summarizes the pharmacological progress of SAL in the treatment of several metabolic (e. g., diabetes and non-alcoholic fatty liver disease) and cardiovascular (e. g., atherosclerosis) diseases in a timely manner to promote the clinical application and basic research of SAL. Accumulating evidence proves that SAL has beneficial effects on these diseases. It can improve glucose tolerance, insulin sensitivity, and β-cell and liver functions, and inhibit adipogenesis, inflammation and oxidative stress. Overall, SAL may be a valuable and potential drug candidate for the treatment of metabolic and cardiovascular diseases. However, more studies especially clinical trials are needed to further confirm its therapeutic effects and molecular mechanisms.     

Correlation between the duration of perphenazine catalepsy and pressure maintained tonic immobility under the influence of beta-sympathotropic agents

In rats the effect of i.p. applied beta-adrenomimetic isoprenaline (ISO) 0.4 mg/kg, sulbutamol (SAL) 2mg/kg, beta-adrenoblocker propranolol (PRO) 2 mg/kg and metipranolol (MET) 4 mg/kg on the duration of perphenazine-induced catalepsy (CAT) and pressure-maintained tonic immobility (TI) was studied. It appeared that a mild constant pressure on the rat body permitted to measure the length of duration of TI in adult rats. The time course of changes in the duration of CAT and TI was repeatedly measured in one-hour intervals with different results. While ISO had no effect on the duration of CAT, SAL prolonged it. Both beta-symathomimetic compounds prolonged the duration of TI. PRO and MET shortened the duration of CAT. PRO did not influence, MET failed in the first phase but in the second phase it significantly prolonged TI duration. In spite of a certain affinity of both phenomena the two, that is, CAT and TI were not parallely influenced by the betasympathotropic agents used.     

Effect of beta1- and beta2-adrenergic stimulation on energy expenditure,substrate oxidation,and UCP3 expression in humans

In humans, beta-adrenergic stimulation increases energy and fat metabolism. In the case of beta1-adrenergic stimulation, it is fueled by an increased lipolysis. We examined the effect of beta2-adrenergic stimulation, with and without a blocker of lipolysis, on thermogenesis and substrate oxidation. Furthermore, the effect of beta1-and beta2-adrenergic stimulation on uncoupling protein 3 (UCP3) mRNA expression was studied. Nine lean males received a 3-h infusion of dobutamine (DOB, beta1) or salbutamol (SAL, beta2). Also, we combined SAL with acipimox to block lipolysis (SAL+ACI). Energy and substrate metabolism were measured continuously, blood was sampled every 30 min, and muscle biopsies were taken before and after infusion. Energy expenditure significantly increased approximately 13% in all conditions. Fat oxidation increased 47 +/- 7% in the DOB group and 19 +/- 7% in the SAL group but remained unchanged in the SAL+ACI condition. Glucose oxidation decreased 40 +/- 9% upon DOB, remained unchanged during SAL, and increased 27 +/- 11% upon SAL+ACI. Plasma free fatty acid (FFA) levels were increased by SAL (57 +/- 11%) and DOB (47 +/- 16%), whereas SAL+ACI caused about fourfold lower FFA levels compared with basal levels. No change in UCP3 was found after DOB or SAL, whereas SAL+ACI downregulated skeletal muscle UCP3 mRNA levels 38 +/- 13%. In conclusion, beta2-adrenergic stimulation directly increased energy expenditure independently of plasma FFA levels. Furthermore, this is the first study to demonstrate a downregulation of skeletal muscle UCP3 mRNA expression after the lowering of plasma FFA concentrations in humans, despite an increase in energy expenditure upon beta2-adrenergic stimulation.     

Combined metformin-salicylate treatment provides improved anti-tumor activity and enhanced radiotherapy response in prostate cancer; drug synergy at clinically relevant doses

BackgroundThere is need for well-tolerated therapies for prostate cancer (PrCa) secondary prevention and to improve response to radiotherapy (RT). The anti-diabetic agent metformin (MET) and the aspirin metabolite salicylate (SAL) are shown to activate AMP-activated protein kinase (AMPK), suppress de novo lipogenesis (DNL), the mammalian target of rapamycin (mTOR) pathway and reduce PrCa proliferation in-vitro. The purpose of this study was to examine whether combined MET+SAL treatment could provide enhanced PrCa tumor suppression and improve response to RT.MethodsAndrogen-sensitive (22RV1) and resistant (PC3, DU-145) PrCa cells and PC3 xenografts were used to examine whether combined treatment with MET+SAL can provide improved anti-tumor activity compared to each agent alone in non-irradiated and irradiated PrCa cells and tumors. Mechanisms of action were investigated with analysis of signaling events, mitochondria respiration and DNL activity assays.ResultsWe observed that PrCa cells are resistant to clinically relevant doses of MET. Combined MET + SAL treatment provides synergistic anti-proliferative activity at clinically relevant doses and enhances the anti-proliferative effects of RT. This was associated with suppression of oxygen consumption rate (OCR), activation of AMPK, suppression of acetyl-CoA carboxylase (ACC)-DNL and mTOR-p70^s6k/4EBP1 and HIF1α pathways. MET + SAL reduced tumor growth in non-irradiated tumors and enhanced the effects of RT.ConclusionMET+SAL treatment suppresses PrCa cell proliferation and tumor growth and enhances responses to RT at clinically relevant doses. Since MET and SAL are safe, widely-used and inexpensive agents, these data support the investigation of MET+SAL in PrCa clinical trials alone and in combination with RT.     

Maternal low-protein diet programs cardiac beta-adrenergic response and signaling in 3-mo-old male offspring

Low birth weight in humans is associated with an increased risk of cardiovascular disease. Humans with heart failure have a reduced beta-adrenergic response. The aim of this study was to investigate the hemodynamic response to the beta-adrenergic agonist isoproterenol and to identify molecular deficiencies that may be predictive of cardiac failure in a low-birth weight rodent model that develops insulin resistance and type 2 diabetes in adulthood. Wistar rats were fed a control or a low-protein (LP) diet throughout pregnancy and lactation. The resting heart rate and blood pressure of the 3-mo-old male offspring of these dams, termed "control" and "LP" groups, respectively, and their responses to isoproterenol (ISO) infusion were monitored by radiotelemetry. The protein expression of beta-adrenergic signaling components was also measured by Western blot analysis. Basal heart rate was increased in LP offspring (P<0.04), although mean arterial pressure was comparable with controls. Chronotropic effects of ISO were blunted in LP offspring with significant delays to maximal response (P=0.01), a shorter duration of response (P=0.03), and a delayed return to baseline (P=0.01) at the lower dose (0.1 microg.kg-1.min-1). At the higher dose (1.0 microg.kg-1.min-1 ISO), inotropic response was blunted (P=0.03) but quicker (P=0.001). In heart tissue of LP offspring, beta1-adrenergic receptor expression was reduced (P<0.03). beta1-Adrenergic receptor kinase and both stimulatory and inhibitory G protein levels remained unchanged, whereas beta-arrestin levels were higher (P<0.03). Finally, insulin receptor-beta expression was reduced in LP offspring (P<0.012). LP offspring have reduced beta-adrenergic responsiveness and attenuated adrenergic and insulin signaling, suggesting that intrauterine undernutrition alters heart failure risk.     

Mechanism of insulin-stimulated clearance of plasma nonesterified fatty acids in humans

Insulin increases plasma nonesterified fatty acid (NEFA) clearance in humans, but whether this is independent of change in plasma NEFA appearance is currently unknown. Nine nondiabetic men (age: 28+/-3 yr, body mass index: 27.2+/-1.7 kg/m2) underwent euglycemic clamps to maintain low (LINS) vs. high (HINS) physiological insulin levels for 6 h. An intravenous infusion of heparin+Intralipid (HI) was performed during 4 of the 6 h of the clamps (in the last 4 h at LINS and in the first 4 h at HINS), whereas saline infusion (SAL) was administered in the remaining 2 h to modulate plasma NEFA levels independently of plasma insulin levels. Four experimental conditions were obtained in each individual: LINS with saline (LINS/SAL) and with HI infusion (LINS/HI) and HINS with saline (HINS/SAL) and with HI infusion (HINS/HI). Plasma palmitate appearance during HINS/SAL was lower than during the three other experimental conditions (P<0.05). In contrast, plasma linoleate appearance, as expected, was increased by HI independently of insulin level (P<0.02). Plasma palmitate clearance during HINS/SAL was higher than LINS/SAL and LINS/HI (P<0.008), and this increase was blunted during HINS/HI. We observed a linear decrease in plasma palmitate clearance with increasing plasma NEFA appearance independent of insulin levels. Plasma NEFA levels increased exponentially with increase in plasma NEFA appearance. We conclude that insulin stimulates plasma NEFA clearance by reducing the endogenous appearance rate of NEFA. The relationship between plasma NEFA level and appearance rate is nonlinear.     

Active and resting metabolism in birds: allometry, phylogeny and ecology

Variation in resting metabolic rate is strongly correlated with differences in body weight among birds. The lowest taxonomic level at which most of the variance in resting metabolic rate and body weight is evident for the sample is among families within orders. The allometric exponent across family points is 0.67. This exponent accords with the surface area interpretation of metabolic scaling based on considerations of heat loss. Deviations of family points from this allometric line are used to examine how resting metabolic rates differ among taxa, and whether variation in resting metabolic rate is correlated with broad differences in ecology and behaviour. Despite the strong correlation between resting metabolic rate and body weight, there is evidence for adaptive departures from the allometric line, and possible selective forces are discussed.
The allometric scaling of active metabolic rate is compared with that of resting metabolic rate. The allometric exponents for the two levels of energy expenditure differ, demonstrating that active small-bodied birds require proportionately more energy per unit time above resting levels than do active large-bodied birds. No consistent evidence was found to indicate that the different methods used to estimate active metabolic rate result in systematic bias. Birds require more energy relative to body size when undertaking breeding activities than at other stages of the annual cycle.     

Isoproterenol increases active lipoprotein lipase in adipocyte medium and in rat plasma

White adipose tissue (WAT) lipoprotein lipase (LPL) activity channels diet fat towards storage in adipocytes. Adrenaline (ADR) is accepted to reduce WAT or adipocyte LPL activity (LPLa), but available data are not clear-cut regarding long exposure to ADR in vitro or in vivo. We studied the effects of long exposures to ADR or beta-adrenergic agonist on LPL: in isolated rat adipocytes (3 h) and in rats (>1 day). Isoproterenol (ISO) (1 microM) did not alter LPLmRNA nor LPLa in adipocytes, but increased LPLa in medium more than twofold (3.58 +/- 0.35 vs. 1.32 +/- 0.35 mU/10(6) adipocytes, P < 0.001). Effect was time (not present at 1 h, clear at 2 h) and concentration dependent (high sensitivity from 10 to 100 nM, max at 1 microM). Adenylate cyclase activator or cyclic AMP (cAMP) analogue produced a similar increase. Thus in adipocytes ISO produced an increase in LPLa release and/or a decrease in extracellular LPLa degradation. ADR or ISO treated rats had a two to fourfold decrease in WAT LPLa vs. unchanged LPLmRNA. This decrease was 10-fold in WAT heparin-releasable LPLa (5.7 +/- 0.6 vs. 57.3 +/- 10.2 mU/g, P < 0.001), which represents peri/extracellular LPLa. Plasma LPLa was increased 11-fold by ADR (3.30 +/- 0.58 vs. 0.32 +/- 0.08 mU/ml, P < 0.001) whereas only threefold by ISO (P > 0.01). We suggest that in vivo ADR increased release of active LPL to plasma from endothelial cells of LPL-rich tissue(s)-WAT was probably one of these tissues releasing LPL since it lost 90% of its peri/extracellular LPLa-and/or decreased degradation of plasma active LPL. Since liver LPLa was not increased, plasma active LPL might be kept away from hepatic degradation by binding to stabilising entities in plasma (fatty acids (FA), lipoproteins or soluble heparan sulphates (HS)). In conclusion, we believe this is the first report stating that: (a) ISO increases LPLa in isolated adipocyte medium, and (b) ADR administration to rats decreases WAT extracellular active LPL and increases preheparin plasma active LPL.     

Respiratory, cardiovascular, and metabolic adjustments to hypoxemia during sleep in piglets

The influence of sleep on ventilation, metabolic rate, cardiovascular function, and regional distribution of blood flow during hypoxemia (PaO2 of 45-50 mm Hg (1 mm Hg = 133.3 Pa)) was studied in piglets at 6+/-1 and 34+/-5 days (mean+/-SD). Measurement of ventilation and metabolic rate was done in a metabolic chamber, and blood flow was measured using the microsphere technique. A subgroup of animals was instrumented for cardiac output measurement (dye-dilution technique) and continuous monitoring of the hemoglobin saturation in oxygen (SaO2). We found that although sleep did not influence the metabolic and cardiac output response to hypoxemia, it affected the ventilatory response as well as the brain and the respiratory muscle blood flows. During active sleep in the older animals, the ventilatory response to hypoxemia was smaller than in the other two states; marked drops in SaO2 occurred with changes in the breathing pattern; and that state was associated with the highest rate of brain blood flow. As well, age affected the ventilatory and metabolic response, but not the cardiovascular response to hypoxemia. The age-dependent ventilatory changes with hypoxemia (smaller ventilatory response in the young than in the older animals) were related to the different levels of oxygen consumption. In summary, active sleep was responsible for all the sleep-dependent changes in the response to a moderate degree of hypoxemia.     

Isoproterenol potentiates exercise-induction of Hsp70 in cardiac and skeletal muscle

The response to exercise stress is characterized by an increase in circulating catecholamines and rapid synthesis of the inducible member of the 70 kDa family of heat shock proteins (Hsp70). Cell culture studies indicate that Hsp70 expression is influenced by beta-adrenergic receptor intermediates including cyclic AMP (cAMP) and cAMP dependent protein kinase (PKA). Thus, in the present investigation, the effect of a beta-adrenergic agonist, isoproterenol (ISO; 10 mg/kg) and a beta-adrenergic antagonist, nadolol (NAD; 25 mg/kg), on the in vivo expression of Hsp70 in rodent cardiac and skeletal muscle following moderate (MOD; 17 m/min) and exhaustive (EXH; 30 m/min) exercise was examined. While ISO alone did not induce Hsp70 synthesis, ISO treatment potentiated Hsp70 expression following MOD in the white vastus and heart (395+/-29 and 483+/-29% greater than control respectively, P < 0.05). Furthermore, this effect was reversed with combined beta-adrenergic agonist and antagonist treatment (ISO+NAD) indicating that the isoproterenol induced increase in post-exercise Hsp70 expression was mediated via beta-adrenergic receptor activity. However, there were no differences in Hsp70 levels among treatment groups following EXH. The failure of NAD to attenuate Hsp70 accumulation following EXH suggests that beta-adrenergic receptor activity is not the main signal in the induction of Hsp70 following exercise. Hsp70 induction was dependent on exercise intensity and ISO administration prior to MOD resulted in Hsp70 levels similar to those observed following EXH. The results from the present investigation indicate that beta-adrenergic receptor stimulation does not induce Hsp70 synthesis per se, but may be one factor involved in the complex regulation of the stress response to exercise in vivo.     

Activation of the constitutive androstane receptor decreases HDL in wild-type and human apoA-I transgenic mice

The nuclear hormone receptor constitutive androstane receptor (CAR, NR1I3) regulates detoxification of xenobiotics and endogenous molecules, and has been shown to be involved in the metabolism of hepatic bile acids and cholesterol. The goal of this study was to address potential effects of CAR on the metabolism of HDL particles, key components in the reverse transport of cholesterol to the liver. Wild-type (WT) mice, transgenic mice expressing human apolipoprotein A-I (HuAITg), and CAR-deficient (CAR(-/-)) mice were treated with the specific CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). CAR activation decreased HDL cholesterol and plasma apolipoprotein A-I (apoA-I) levels in both WT and HuAITg mice, but not CAR(-/-) mice. Both mouse apoA-I and human apoA-I were decreased by more than 40% after TCPOBOP treatment, and kinetic studies revealed that the production rate of HDL is reduced in TCPOBOP-treated WT mice. In transient transfections, TCPOBOP-activated CAR decreased the activity of the human apoA-I promoter. Although loss of CAR function did not alter HDL levels in normal chow-fed mice, HDL cholesterol, apoA-I concentration, and apoA-I mRNA levels were increased in CAR(-/-) mice relative to WT mice when both were fed a high-fat diet. We conclude that CAR activation in mice induces a pronounced decrease in circulating levels of plasma HDL, at least in part through downregulation of apoA-I gene expression.     

Cardiovascular effects of bPTH-(1-34) and isoproterenol in the frog, Rana tigrina.

1. The cardiovascular effects of bovine parathyroid hormone fragment [bPTH-(1-34)] and isoproterenol (ISO) on frog (Rana tigrina) isolated atria and helical strips of blood vessels were examined since PTH produces a beta-adrenergic-like effect in the mammal. 2. Data showed that both bPTH-(1-34) and ISO were vasorelaxant in KCl and arginine vasoctocin (AVT) preconstricted dorsal aorta, iliac and femoral arteries. 3. They both relaxed extracellular calcium-dependent contrations. 4. There was no additive nor synergistic effect between them in AVT preconstricted strips. 5. Both bPTH-(1-34) and ISO were positively inotropic but differed in their chronotropic effects, being negative and positive. 6. In the tiger frog, bPTH-(1-34) shows beta-adrenergic like contractile responses in both the cardiac and vascular smooth muscle as in the mammal, but not in the heart rate.     

Brown adipose tissue cell respiration in hypo- and hyperthyroidism after stimulation with selective and non selective beta-adrenergic agonists.

Brown adipocyte respiration was measured in isolated cells from hypothyroid, hyperthyroid and euthyroid Sprague-Dawley male rats. Hypothyroidism was induced by providing drinking water containing methimazole and hyperthyroidism was induced by addition of thyroid powder to the diet. Brown adipose tissue (BAT) cells were isolated by collagenase digestion and oxygen consumption (VO2) was measured by Clark type oxygen electrodes. BAT cell respiration was stimulated by selective and nonselective beta-adrenergic agonists: BRL 35135A (BRL) and Isoprenaline (ISO). Basal BAT cells respiration did not differ according to thyroid status. Maximal VO2 responses of BAT adipocytes from hypothyroid rats were significantly lower than in euthyroidism after ISO and BRL. The reduced response was more marked for ISO than for BRL. The thermogenic sensitivity was significantly greater in euthyroid than is hypothyroid cells for ISO, but not for BRL. The euthyroid-hyperthyroid differences were not significantly different. These results suggest: basal respiration of BAT cells in hypo- and hyperthyroidism does not reflect the overall changes in whole body metabolism; the decreased thermogenic response in hypothyroidism might be due to decreased beta-adrenoceptor numbers and/or decreased intracellular thyroxine-triiodothyronine conversion; changes in sensitivity to ISO and BRL in vitro reflect the changes seen in VO2 in vivo.     

Discrepancies between the affinities of binding and action of the novel beta-adrenergic agonist BRL 37344 in rat brown adipose tissue

The novel brown adipose tissue (BAT) selective beta-adrenergic agonist, BRL 37344, is 31-fold more potent than (-)-isoproterenol in stimulating the respiratory rate of interscapular BAT fragments. BRL 37344 is also more potent (9-fold) than (-)-isoproterenol in stimulating adenylate cyclase activity of IBAT purified plasma membranes whereas, in the same preparation, it is 81-fold less potent than (-)-isoproterenol in competition displacement studies with the beta-adrenergic ligand, [125I]cyanopindolol. We have previously demonstrated that the photoaffinity reagent [125I]cyanopindolol-diazirine selectively labels a 62 kDa protein in IBAT plasma membranes that displays pharmacological properties of a beta 1-adrenergic subtype. Relatively high concentrations of BRL 37344 (10 microM) are required to displace [125I]cyanopindolol-diazirine binding to the 62 kDa protein. Taken together, the results suggest that two different populations of beta-adrenergic receptors may co-exist in BAT plasma membranes: a small population (about 15%) of atypical beta-receptors and a large population of beta 1-receptors that exhibit high and low affinities for BRL 37344, respectively.     

Effects of the infusion of non-selective beta-, and selective beta1- or beta2-adrenergic agonists, on body fat mobilisation in underfed or overfed non-pregnant heifers.

The aim of this study was to analyse the effects of the intravenous infusion of a non-selective beta-agonist (beta-A) (isoproterenol, ISO), and selective beta1-A (dobutamine, D) or beta2-A (terbutaline, T) on body fat mobilisation in non-pregnant heifers, in a 2 x 2 crossover design with two treatments (underfeeding or overfeeding) and two periods. The effect of the duration of submission to each energy level on basal and ISO-induced fat mobilisation was also studied. ISO had a high and significant lipolytic effect whatever the energy level. Nevertheless, the response area of non-esterified fatty acids (NEFA) to ISO in underfed cows was 1.7 times greater than that in overfed cows. T had a slight but significant lipolytic effect on NEFA plasma response in the underfed group. D had no lipolytic effect. Basal and ISO-stimulated plasma NEFA levels were similar after 1 or 4 weeks of underfeeding.     

Atrial natriuretic factor release during acute infusion of isoproterenol in the conscious rat.

The effect of beta-adrenergic stimulation on atrial natriuretic factor (ANF) release was studied in conscious rats. 20-min infusion of 85 or 850 ng kg-1 min-1 isoproterenol (ISO) resulted in positive inotropic and chronotropic responses and no elevation of atrial pressures. A slight increase in plasma ANF, together with a drop in blood pressure, were observed only in the group infused with the higher dose. During the infusion of 850 ng kg-1 min-1 ISO, there was no relationship between plasma ANF and any of the haemodynamic parameters, with the exception of mean arterial pressure (r = 0.72, P less than 0.05, n = 9). Larger doses (greater than 3 micrograms kg-1 min-1) were toxic. We conclude that beta-adrenergic stimulation is not an important stimulus for ANF release when diastolic resting tension is low.     

Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha

Animal studies reveal that fasting and caloric restriction produce increased activity of specific metabolic pathways involved in resistance to weight loss in liver. Evidence suggests that this phenomenon may in part occur through the action of the constitutive androstane receptor (CAR, NR1I3). Currently, the precise molecular mechanisms that activate CAR during fasting are unknown. We show that fasting coordinately induces expression of genes encoding peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), CAR, cytochrome P-450 2b10 (Cyp2b10), UDP-glucuronosyltransferase 1a1 (Ugt1a1), sulfotransferase 2a1 (Sult2a1), and organic anion-transporting polypeptide 2 (Oatp2) in liver in mice. Treatments that elevate intracellular cAMP levels also produce increased expression of these genes in cultured hepatocytes. Our data show that PGC-1alpha interaction with hepatocyte nuclear factor 4alpha (HNF4alpha, NR2A1) directly regulates CAR gene expression through a novel and evolutionarily conserved HNF4-response element (HNF4-RE) located in its proximal promoter. Expression of PGC-1alpha in cells increases CAR expression and ligand-independent CAR activity. Genetic studies reveal that hepatic expression of HNF4alpha is required to produce fasting-inducible CAR expression and activity. Taken together, our data show that fasting produces increased expression of genes encoding key metabolic enzymes and an uptake transporter protein through a network of interactions involving cAMP, PGC-1alpha, HNF4alpha, CAR, and CAR target genes in liver. Given the recent finding that mice lacking CAR exhibit a profound decrease in resistance to weight loss during extended periods of caloric restriction, our findings have important implications in the development of drugs for the treatment of obesity and related diseases.     

Structure-activity relationships of some selected beta-adrenergic blocking agents--oxidation with N-bromosuccinimide.

A relationship between in vitro rate of oxidation by N-bromosuccinimide (NBS) and the pharmacologic activity (pA2) of different beta-adrenergic blockers for different blocking agent-tissue combinations has been studied. The rates of oxidation of the alcoholic group in the drugs by NBS, as well as their molecular conformations as represented by molecular models, were studied in order to determine requirements for selectivity and potency of action of beta-adrenergic blocking agents. Using data from all 7 drugs studied--both nonselective and selective blocking agents--no significant correlation between pA2 and -log k2 (k2 is the second order rate constant for the oxidative reaction) was found. If data from only the 4 nonselective agents were used (16 drug-tissue combinations), a correlation significant at p less than 0.01 was found. Hypotheses are presented to account for the selective action of some beta-adrenergic blocking agents.