Adrenergic Agonist Terbutaline Research Articles

Effect of beta2 -adrenergic agonist and resistance training on maximal oxygen uptake and muscle oxidative enzymes in men.

While beta2 -adrenoceptor stimulation has been shown to increase lean mass and to alter metabolic properties of skeletal muscle, adaptations in muscle oxidative enzymes and maximal oxygen uptake ( O2max ) in response to beta2 -adrenergic agonist treatment are inadequately explored in humans, particularly in association with resistance training. Herein, we investigated beta2 -adrenergic-induced changes in O2max , leg and arm composition, and muscle content of oxidative enzymes in response to treatment with the selective beta2 -adrenergic agonist terbutaline with and without concurrent resistance training in young men. Forty-six subjects were randomized to 4weeks of lifestyle maintenance (n=23) or resistance training (n=23). Within the lifestyle maintenance and resistance training group, subjects received daily terbutaline (8×0.5mg) (n=13) or placebo (n=10) treatment. No apparent treatment by training interactions was observed during the study period. Terbutaline increased leg and arm lean mass with the intervention, whereas no treatment differences were observed in absolute O2max and incremental peak power output (iPPO). Treatment main effects were observed for O2 -reserve (P<.05), O2max relative to body mass (P<.05), O2max relative to leg lean mass (P<.01), and iPPO relative to leg lean mass, in which terbutaline had a negative effect compared with placebo. Furthermore, content of electron transport chain complex I-V decreased by 11% (P<.05) for terbutaline compared with placebo. Accordingly, chronic treatment with the selective beta2 -adrenergic agonist terbutaline may negatively affect O2max and iPPO in relative terms, but not in absolute.

SAT-078 Adrenergic Receptor Regulation of Intracellular Calcium in Human Adrenocortical Carcinoma HAC15 Cells

Intracellular calcium fluctuations may play a role in the control of corticosteroid synthesis and secretion by the adrenal cortex. Using live-cell imaging with the calcium-sensitive fluorescent probe Fluo-4 in a human adrenocortical carcinoma cell line (HAC15), we previously demonstrated that activation of M3 muscarinic receptors stimulates intracellular calcium oscillations, enhances aldosterone production, and increases expression of CYP11B2 (1). To further understand autonomic control of cortical cell function, we are investigating the role of adrenergic signalers in regulating calcium homeostasis in HAC15 cells. Activation of adrenergic receptors with the endogenous, non-selective agonists norepinephrine and epinephrine (10μM) causes single, large calcium transients that do not oscillate. A similar calcium response results from the alpha adrenergic agonist phenylephrine, while the beta adrenergic agonist terbutaline does not elicit calcium changes. Consistent with this, norepinephrine-induced calcium changes are blocked by the alpha adrenergic antagonist phentolamine, but not by the beta adrenergic antagonist propranolol. Taken together, these preliminary results suggest that alpha adrenergic receptors are the dominant adrenergic subtype in the human adrenal cortex. Further experiments will use radiolabel binding assays, subtype-selective alpha receptor modulators, and RT-PCR methods, to determine which alpha subtypes are present. Also, ELISA measurements of steroid production will determine the physiological consequence of adrenergic receptor activation.

The role of Cl− in the regulation of ion and liquid transport in the intact alveolus during β‐adrenergic stimulation

The epithelium of the developing lung displays an evolving liquid transport phenotype, in which Cl(-) secretion during fetal life is rapidly switched to Na(+) absorption perinatally. However, the mechanisms underlying the homeostasis of the thin layer of liquid lining the postnatal pulmonary epithelium remain elusive. In particular, it remains unclear whether the stimulated clearance of excess alveolar liquid is mediated via transepithelial Cl(-) transport. Our study is a pharmacological analysis with the aim of addressing this issue, which is of major physiological significance in cases of pulmonary oedema from any cause. We measured the rate of transepithelial liquid movement (J(v)) with (125)I-albumin, in the in situ perfused adult rat lung. Transepithelial Cl(-) transport was studied with the use of the Cl(-) channel inhibitor NPPB in the resting state and during stimulation with the β(2)-adrenergic agonist terbutaline. The study of J(v) in these conditions revealed the following findings: (1) there is net absorption of excess of alveolar liquid in the resting, unstimulated state, which is predominantly amiloride sensitive; (2) inhibition of Cl(-) transport with NPPB in the resting state results in a 1.6-fold increase in net absorption of alveolar liquid; and (3) the terbutaline-stimulated net absorption of the excess liquid is enhanced by 2.8-fold in the presence of NPPB. Our results are suggestive of the functional presence of secretory, but not absorptive, Cl(-) mechanisms and show that transepithelial Cl(-) transport is not part of the mechanism underlying lung liquid clearance in response to β-adrenergic stimulation.

Characterization of bovine neutrophil β2‐adrenergic receptor function

This study compares bovine leukocyte beta-adrenergic receptor densities to that of the rat, demonstrates for the first time a functional beta(2)-adrenergic receptor signaling pathway in steer neutrophils, and investigates the effect of an inflammatory stimulus on that signaling pathway. The beta(1)-/beta(2)-adrenergic antagonist ([3H])CGP-12177 demonstrated that rat lymphocyte specific binding-site density was highest, followed by steer and dairy cow lymphocytes, and lastly steer and dairy cow neutrophils. The beta(2)-adrenergic agonist terbutaline stimulated steer neutrophil adenosine 3,5-cyclic monophosphate (cAMP) production, an effect increased by inclusion of > or = 1 x 10(-8) M phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C. Both terbutaline and the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) independently decreased steer neutrophil superoxide anion production in a concentration-dependent manner, with 1 x 10(-4) M IBMX enhancing both the potency and efficacy of the terbutaline effect (up to 74% reduction in superoxide anion production). Superoxide anion production was also reduced by the synthetic cAMP analog 8-bromo-cAMP, which increased the potency of the IBMX effect on superoxide anion production. Taken together, these data demonstrate the presence of a beta(2)-adrenergic receptor signaling pathway in bovine neutrophils much like that described in other animal species, as well as the potential for an inflammatory stimulus to alter its function.

Beta adrenergic inhibition of capsaicin-induced, NK 1 receptor-mediated nerve growth factor biosynthesis in rat skin

Excitation of primary afferent neurons stimulates the expression of cytokines and nerve growth factor (NGF) in innervated tissues. Since NGF is a neurotrophic and immunomodulatory factor contributing to inflammatory hyperalgesia and tissue response to injury, this study was conducted in order to investigate the mechanisms by which afferent neuron stimulation by topical application of capsaicin increases NGF in the rat skin. Thereby it was sought to identify possible targets for pharmacological modulation of NGF biosynthesis. Topical capsaicin (>1 mg/ml ethanol) caused a concentration- and time-dependent increase in the concentration of NGF in rat skin. The capsaicin-induced increase of NGF was not significantly affected by indomethacin administered at a dose (2 mg/kg) that abolishes prostaglandin E 2 biosynthesis. The NGF increase was suppressed by treatment of rats with the selective tachykinin NK 1 receptor antagonist SR140333 (0.1 mg/kg), and by the beta adrenergic agonist terbutaline (0.3 mg/kg). The effect of terbutaline was reversed by the beta adrenergic antagonist propranolol (1 mg/kg). Terbutaline also inhibited the increase in NGF caused by intraplantar injection of the NK 1 receptor agonist substance P (SP), but did not significantly affect that caused by carrageenan. The results show that topical administration of capsaicin causes a primarily NK 1 receptor-dependent increase in the NGF content of rat skin, which is susceptible to inhibition by beta adrenergic agonists. These observations not only suggest regulation of skin NGF biosynthesis by afferent neuronal and adrenergic mechanisms, but also indicate possible targets for pharmacological modulation of skin NGF biosynthesis.

Effects of norepinephrine on rat cultured microglial cells that express α1, α2, β1 and β2 adrenergic receptors

Microglial cells rapidly become activated in response to even minor damage of neurons, suggestive of the intimate interactions between neurons and microglial cells. Although mediators for microglia–neuron interactions have not been well identified, neurotransmitters are possible candidates transmitting signals from neurons to microglial cells. Among the neurotransmitters, we focused on the effects of norepinephrine and other adrenergic agonists on the functions of rat cultured microglial cells. Reverse transcriptase polymerase chain reaction studies revealed that microglial cells expressed mRNAs encoding α1A, α2A, β1 and β2 receptors. Norepinephrine and a β2 adrenergic agonist terbutaline elevated intracellular cAMP level of microglial cells. Norepinephrine, an α1 agonist phenylephrine, a β1 agonist dobutamine and terbutaline suppressed the expressions of mRNAs encoding pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor α. Release of tumor necrosis factor α and nitric oxide was suppressed by norepinephrine, phenylephrine, dobutamine and terbutaline. An α2 agonist clonidine and dobutamine upregulated the expression of mRNA encoding catechol-O-methyl transferase, an important enzyme to degrade norepinephrine. Norepinephrine, dobutamine and terbutaline upregulated the expressions of mRNA encoding 3-phospshoglycerate dehydrogenase, an essential enzyme for synthesis of l-serine and glycine, which are amino acids necessary for neuronal survival. Clonidine upregulated the expression of mRNA encoding an anti-apoptotic factor Bcl-xL. These results suggest that norepinephrine participates in the regulation of brain function at least partly by modulating the functions of microglia.

Effects of terbutaline on NGF formation in allergic inflammation of the rat.

1. The aim of this study was to determine the effects of the beta adrenergic agonist terbutaline on NGF increase caused by allergic inflammation in rats. 2. Intraplantar antigen injection in sensitized rats increased paw volume and stimulated NGF biosynthesis in the skin of the injected paw as determined 3 and 6 h after injection. Treatment of rats with terbutaline (0.1 - 0.3 mg kg(-1), s.c.) had no significant effect on the NGF concentration in non-inflamed skin, but reduced oedema, and at 0.3 mg kg(-1) also NGF mRNA and immunoreactive NGF in the skin of the inflamed paw in a propranolol-reversible manner. In carrageenan-induced inflammation, terbutaline did not significantly reduce the inflammation-induced increase of NGF in paw skin. 3. Exposure of sensitized rats to aerosolized antigen (twice, 24 h interval) increased protein content, eosinophil leukocytes, and immunoreactive NGF in the bronchoalveolar lavage fluid (BAL, obtained 16 h after the second antigen exposure). Treatment of rats with terbutaline (0.3 mg kg(-1), s.c. 30 min before the second antigen challenge) suppressed antigen-induced elevation of protein and eosinophil leukocytes, and reduced the concentration of NGF in BAL to values similar to those found in non-sensitized rats. 4. The present results demonstrate anti-allergic properties of terbutaline in rats that were accompanied by a marked reduction of antigen-induced NGF increase in skin and BAL, respectively. These results are compatible with the assumption that terbutaline primarily suppressed the immune response to antigen thereby attenuating the release of vasoactive mediators and the stimulation of NGF biosynthesis.

Clinical pharmacokinetics of bambuterol.

Bambuterol, a biscarbamate ester prodrug of the beta 2 adrenergic agonist terbutaline, has been approved for the treatment of asthma in 28 countries. It is available in 10 and 20mg (25 and 50 mumol) tablets as the hydrochloride salt. Bambuterol is stable to presystemic elimination and is concentrated by lung tissue after absorption from the gastrointestinal tract. The prodrug is hydrolysed to terbutaline primarily by butyrylcholinesterase, and lung tissue is capable of this metabolic pathway. It is also oxidatively metabolised to products which can be hydrolysed to terbutaline. Peak terbutaline plasma concentrations occur 3.9 to 6.8 hours after bambuterol ingestion, and the peak: trough terbutaline concentration ratio is lower than that after ingestion of terbutaline. Older patients have a greater area under the plasma concentration-time curve for terbutaline over a dose interval at steady-state. Whether genetic variations in the expression of butyrylcholinesterase alter therapeutic response remains to be determined. The efficacy of bambuterol has been demonstrated to last for 24 hours after ingestion; once-daily administration in the evening is recommended. Maximum therapeutic benefit requires more than 1 week of treatment. Except for the suppression of plasma butyrylcholinesterase, the adverse effect profile of bambuterol is essentially that of a beta 2 agonist and is best correlated with circulating terbutaline concentration in plasma. Plasma butyrylcholinesterase activity returns to control values approximately 2 weeks after discontinuation of treatment with bambuterol. This new drug provides oral beta 2 agonist therapy in a more convenient form than was available previously, and may have a better therapeutic: toxic ratio than terbutaline.

Role of norepinephrine in suppressed IgG production in epilepsy-prone mice

The responses of two substrains of Balb/c mice (Epilepsy Prone and Epilepsy Resistant) to immunization with sheep red blood cells (SRBC) were examined to determine whether chronic neurochemical differences between the two strains could influence B cell function. Anti-SRBC IgG production in the Epilepsy Prone (EP) strain was reduced relative to the Epilepsy Resistant (ER) strain, while anti-SRBC IgM production was unaffected. No differences were found in in vitro antibody (Ab) production or T lymphocyte function between the EP and ER strains, suggesting that in vivo conditions rather than an intrinsic cellular defect are responsible for reduced IgG production by EP mice. Basal splenic norepinephrine (NE) levels were significantly higher in EP mice than those in ER mice, and remained significantly higher following immunization. ER mice treated with the β 2 adrenergic agonist terbutaline on days 4, 5 and 6 after immunization produced significantly lower numbers of IgG PFC than did saline treated controls. Addition of NE during later stages of in vitro immunization suppressed both anti-SRBC IgM and IgG production by splenic lymphocytes from Balb/c mice, and NE was found to decrease IFNγ production. These observations suggest that dysregulation of splenic NE can have an impact on the immune response.

Beta adrenergic influence on oesophageal peristalsis in man.

The effects of the beta-1 adrenergic agonist prenalterol and the beta-2 adrenergic agonist terbutaline on oesophageal peristalsis were studied in nine healthy volunteers with pressures recorded in the proximal, middle, and distal oesophagus. Two doses of the agonists were given after pretreatment with placebo, propranolol, or metoprolol in a double blind randomised fashion. Terbutaline 0.25 +/- 0.25 mg iv decreased peristaltic pressure in middle oesophagus from 8.1 +/- 1.1 to 5.1 +/- 0.8 kPa (p less than 0.01) and in the distal oesophagus from 9.5 +/- 1.0 to 4.7 +/- 0.6 kPa (p less than 0.001). Peristaltic velocity was decreased in the distal oesophagus after terbutaline from 3.3 +/- 0.2 cm/sec to 2.9 +/- 0.2 cm/sec (p less than 0.05). Prenalterol 1 mg iv was followed by a decrease of peristaltic pressure in the middle oesophagus from 10.2 +/- 1.3 to 7.7 +/- 1.1 kPa (p less than 0.01) and a decrease of peristaltic velocity in upper oesophagus from 3.6 +/- 0.2 to 3.3 +/- 0.1 cm/sec (p less than 0.05) while no significant changes were seen in the distal oesophagus. Pretreatment with the beta-1 blocker metoprolol 15 mg iv blocked the effects of prenalterol 1 mg iv but not the effects of terbutaline. Propranolol 10 mg iv blocked the effects of terbutaline on peristaltic pressure. After metoprolol infusion mean distal peristaltic amplitude was 11.9 +/- 0.8 kPa compared with 8.5 +/- 1.2 kPa after placebo (p less than 0.01). It is concluded that both beta-1 and beta-2 adrenoceptor stimulation significantly decrease oesophageal peristaltic pressure in man. The body of the oesophagus seems to be under beta adrenergic inhibitory influence under physiological conditions.

Isolation and culture of human alveolar type II epithelial cells. Characterization of their phospholipid secretion.

Alveolar type II epithelial cells have been isolated previously from rodents but not from humans. The aims of this study were to isolate and culture alveolar type II cells from human lungs, and to study their phospholipid secretion. Lung tissue was obtained from 13 patients after lobectomy or pneumonectomy. Type II cells were isolated by a modification of our method for isolating rat type II cells with porcine pancreatic elastase and discontinuous metrizamide density gradients. Cells were purified further by differential adherence and they were then cultured on an extracellular matrix prepared from bovine corneal endothelial cells. We obtained 1.3 to 4.8 X 10(6) cells per gram of tissue with cell viability on the day of isolation of 96 +/- 1% (mean +/- SE, n = 10). Type II cell purity, assessed by Papanicolaou stain on Day 1 in culture, was 84 +/- 4% (mean +/- SE) in 9 of the 13 experiments. In the remaining 4 experiments, the purity was less than 50%. Electron microscopy showed well-preserved ultrastructure. The cells, radiolabeled with 32Pi, secreted the phospholipids characteristic of pulmonary surfactant, primarily phosphatidylcholine (68%) and phosphatidylglycerol (12%). Phospholipid secretion was stimulated by tetradecanoyl phorbol acetate (4.5 times baseline) and by the beta adrenergic agonist terbutaline (2.0 times baseline), but not by the cholinergic agonist carbamylcholine chloride. In summary, human alveolar type II epithelial cells can be isolated from resected lung and maintained in culture, and they secrete the phospholipids characteristic of pulmonary surface active material.