Beta 2-adrenoceptor Agonist Terbutaline Research Articles

The beta2-adrenoceptor agonist terbutaline specifically decreases pulmonary arterial pressure by alpha-adrenoceptor antagonism

The beta2-adrenoceptor agonist terbutaline specifically decreases pulmonary arterial pressure by alpha-adrenoceptor antagonism

Polymorphism of the AHSG gene is associated with increased adipocyte β2-adrenoceptor function

The alpha(2) Heremans-Schmid glycoprotein (AHSG) gene is implicated in the regulation of body fat and insulin sensitivity. The Met/Met genotype of the common single-nucleotide polymorphism (SNP), rs4917, in the AHSG gene has been shown to be associated with reduced plasma levels as well as lower body fat. Here, we studied the association of this variation with subcutaneous adipocyte lipolysis. Ninety-three obese and nonobese healthy men were genotyped for Thr230Met, and subcutaneous adipose tissue biopsies were analyzed for lipolysis characteristics. The Met/Met genotype was associated with a marked increase of 1.5 log units in the lipolytic sensitivity to the beta2-adrenoceptor agonist terbutaline (P=0.0008) as compared with the Thr/Thr and Thr/Met genotypes. This corresponds to an approximately 35-fold increase in beta2-adrenoceptor function. The genotype effect was independent of body mass index and waist circumference. In contrast, lipolytic sensitivity to both the beta1-adrenoceptor agonist dobutamine (P=0.25) and the alpha2A-adrenoceptor agonist clonidine (P=0.54) was unaffected by the Thr230Met variation. Moreover, no difference in either maximal stimulation or inhibition of lipolysis was found between genotypes. We conclude that a common variation (Thr230Met) in the AHSG gene is associated with a marked increase in beta2-adrenoceptor sensitivity in subcutaneous fat cells, which may be of importance in body weight regulation.

Synergism between beta 2-adrenoceptor agonists and subtype-selective alpha 1A-adrenoceptor antagonists in the tocolytic effect on pregnant rat uterus in vitro.

1. Despite great efforts in recent decades, premature birth is still a leading cause of perinatal morbidity and mortality. beta2-Adrenoceptor agonists are frequently used as tocolytics, although their use is rather controversial. Previous animal studies have revealed that blockade of alpha1A-adrenoceptors results in relaxation of the pregnant rat myometrium. 2. The aim of the present study was to investigate the uterus relaxant effect of the beta2-adrenoceptor agonists (terbutaline, ritodrin) applied together with the subtype-selective alpha1A-adrenoceptor antagonists (WB 4101, 5-methylurapidil) in an in vitro rat model. The main objective of the experiments was to clarify whether there was an additive or a potentiating synergism between the two drug classes. 3. Myometrial rings were taken from female, 22-day pregnant (end-term) Sprague-Dawley rats. Electrical field stimulation (EFS) was used to elicit rhythmical contractions. Non-cumulative concentration-response curves were constructed to the beta2-adrenoceptor agonists and the alpha1A-adrenoceptor antagonists alone and to beta2-adrenoceptor agonists co-administered with the alpha1A-adrenoceptor antagonists. 4. Both groups of drugs inhibited EFS-induced contractions in a dose-dependent way. Administering the beta2-adrenoceptor agonists in combination with the alpha1A-adrenoceptor antagonists resulted in a significant decrease in the EC50 and an increase in the maximal contraction inhibiting effect. 5. The potentiating synergism that has been revealed between beta2-adrenoceptor agonists and alpha1A-adrenoceptor antagonists in the uterus relaxant effect may be of great clinical importance because it could improve the efficacy of therapy of preterm delivery.

Effects of a range of beta2 adrenoceptor agonists on changes in intracellular cyclic AMP and on cyclic AMP driven gene expression in cultured human airway smooth muscle cells.

1. The effects of the selective beta2 adrenoceptor agonists salbutamol, terbutaline and salmeterol and the non-selective beta adrenoceptor agonist isoprenaline on [3H]-cyclic AMP formation and cyclic AMP response element (CRE) driven luciferase expression, assessed using the construct p6CRE/luc, were studied in primary cultures of human airway smooth muscle (HASM) cells. 2. Optimal transfection conditions for transient expression of pGL3 Control were 4 microg DNA/well71 in a 6 well plate and 1.8 microl Transfectam/microg DNA. Expression was maximal at 48 - 72 h. 3. Salbutamol (maximum response 19%, EC50 0.6 microM), terbutaline (maximum response 38%, EC50 2.3 microM) and salmeterol (maximum response 18%, EC50 0.0012 microM) were all partial agonists for cyclic AMP formation compared with isoprenaline (EC50 0.08 microM). However, all of the beta2 adrenoceptor agonists produced increases in CRE-driven luciferase activity, in cultured HASM transfected with the vector p6CRE/luc, which were equivalent or greater (salmeterol) than those seen with isoprenaline. 4. Both salbutamol and salmeterol were more potent at increasing luciferase expression than in elevating cyclic AMP levels in these cells. The potency ratios (EC50 (cyclic AMP)/EC50 (LUC)) for the agents studied were isoprenaline: 0. 2 fold, terbutaline: 3 fold, salbutamol: 24 fold, salmeterol: 38 fold. 5. These data suggest that important quantitative differences exist in the ability of beta2 adrenoceptor agonists to increase whole cell cyclic AMP levels in airway smooth muscle and to drive gene expression via a CRE-driven mechanism.

Beta2-adrenoceptors mediate melanosome dispersion in winter flounder (Pleuronectes americanus))

Although the melanosome-aggregating mediation of catecholamines through alpha -adrenoceptors is well established for teleost melanophores, the regulation of the dispersive process is not as clearly understood. The melanosome-aggregating effect of high concentrations of catecholamines in vitro is reversed at low concentrations with melanophores of the winter flounder, Pleuronectes americanus. In vitro incubation in low concentrations of isoproterenol ( <<= 10-7M) and noradrenaline ( <<= 10-8M) enhances Na+-induced melanosome dispersion in balanced salt solution, which can be depressed by propranolol (10-4M), indicating beta -adrenoceptor mediation in pigment dispersion. The subtype of this adrenoceptor appears to be the beta2conformation, since the beta2-adrenoceptor agonist terbutaline (>=>3.15 times 10-6M) reverses the melanosome-aggregating effect associated with higher concentrations of noradrenaline and with electrical stimulation. It is concluded that in this species there is adrenergic neuronal control of melanosome aggregation through alpha -adrenoceptors on release of noradrenaline and of dispersion through beta2-adrenoceptors during a subsequent decrease in concentration.

Chronic terbutaline treatment desensitizes beta-adrenergic inhibition of lymphocyte activation in healthy volunteers.

1. A substantial body of evidence has accumulated that beta-adrenoceptor mediated increases in human lymphocyte cyclic AMP can inhibit activation of resting lymphocytes. The aim of this study was to determine whether this effect might desensitize during chronic beta-adrenoceptor agonist treatment. We assessed the effects of 2 weeks treatment with the beta 2-adrenoceptor agonist terbutaline (3 x 5 mg day-1 p.o.) on isoprenaline-induced inhibition of concanavalin A-evoked lymphocyte activation in nine healthy male volunteers. Lymphocyte activation was determined by [3H]-thymidine incorporation (as a measure of proliferation), and inositol phosphate formation was assessed in [3H]-myo-inositol prelabelled lymphocytes in the presence of 10 mM LiCl. 2. Terbutaline treatment caused a significant reduction in isoprenaline (1 nM-10 microM)-induced increases in lymphocyte cyclic AMP content; the maximal increase was 14 +/- 3 pmol/10(6) cells before and 7 +/- 2 pmol/10(6) cells (n = 9, P < 0.05) after terbutaline treatment. 3. The mitogen concanavalin A (Con A, 1-32 micrograms ml-1)-induced increase in inositol phosphate formation was significantly enhanced after terbutaline treatment (max. increase before treatment: 255 +/- 25% above basal; after treatment 453 +/- 16% above basal; n = 9, P < 0.001), while isoprenaline (1 nM-10 microM)-induced inhibition of Con A (16 micrograms ml-1)-evoked increases in inositol phosphate formation was significantly reduced after the terbutaline treatment (max. inhibition before treatment: 22 +/- 4%; after treatment 9 +/- 1%, n = 9, P < 0.01). 4. Con A (1.25-10 micrograms ml-1)-induced increases in [3H]-thymidine incorporation into the lymphocytes (as a measure of proliferation) was not affected by the terbutaline treatment. On the other hand, isoprenaline (1 nM-1 microM)-induced inhibition of Con A (5 micrograms ml-1)-evoked lymphocyte proliferation (max. inhibition: 33 +/- 7%, n = 9) was almost completely abolished after the terbutaline treatment. 5. We conclude that chronic treatment with terbutaline desensitizes lymphocyte beta 2-adrenoceptors and, therefore, the inhibitory effect of cyclic AMP on lymphocyte activation.

Effect of adrenaline and alpha-agonists on net rate of liquid absorption from the pleural space of rabbits.

Indirect evidence supporting a solute-coupled liquid absorption from the pleural space of rabbits has recently been provided; moreover, the beta 2-adrenoceptor agonist terbutaline has been found to increase this absorption. In this study the effect of adrenaline and alpha-adrenoceptor agonists on net rate of liquid absorption (Jnet) from albumin Ringer hydrothoraces of various sizes has been determined in anaesthetized rabbits. In hydrothoraces with adrenaline (5 x 10(-6) M) the relationship between Jnet and volume of liquid injected was displaced upwards by 0.09 ml h-1 relative to that in control hydrothoraces (P < 0.01). This displacement did not occur with lower adrenaline concentrations or after pretreatment with the beta-blocker propranolol. Hence, this increase in Jnet is mediated by stimulation of beta-receptors. It seems to be caused by an increase in solute-coupled liquid absorption, since beta-agonists inhibit lymphatic activity while, at relatively high concentrations, they may increase active transport. Conversely, the strong stimulation of lymphatic alpha-receptors that should occur with adrenaline after beta-blockade may fail to increase lymphatic drainage, because it has been shown that the increase in contraction frequency of lymphatics may be balanced by the decrease in their stroke volume. Arterial blood pressure during the hydrothoraces with adrenaline was unchanged. In hydrothoraces with the alpha 2-agonist clonidine (5 x 10(-6) M; a less potent agent than adrenaline) the slope of the relationship between Jnet and volume injected increased by 26% (P < 0.01), while its origin did not change. This increase in slope did not occur with a lower clonidine concentration or after pretreatment with the alpha-blocker phentolamine. Hence, it is caused by stimulation of alpha 2-receptors, which probably lead to an increase in lymphatic drainage related to liquid load. In hydrothoraces with the alpha 1-agonist phenylephrine (5 x 10(-6) or 10(-7) M) Jnet was simlar to control values.

K+ balance during exercise and role of beta-adrenergic stimulation.

Infusion of the beta 2-adrenoceptor agonist terbutaline will cause an activation of the Na(+)-K+ pump that leads to lowering of plasma K+ concentration and intracellular Na+ concentration. The present study examines whether these changes will affect the K+ homeostasis during subsequent exercise. Two-legged knee-extension exercise was carried out at low (40 W) and high (75 W) power for 8 min in six healthy, male subjects before (control) and during intravenous infusion of terbutaline (priming dose 500 micrograms, sustained dose 4.1 micrograms/min). Catheters in the femoral vein and artery allowed blood sampling and continuous recording of femoral venous plasma K+ concentration ([K+]fv) by means of a pliable, K(+)-sensitive electrode. Leg blood flow was measured by bolus injections of indocyanine green. Terbutaline decreased arterial K+ concentration by 0.83 mmol/l. The femoral veno-arterial concentration difference for K+ and loss rates of K+ were not significantly affected by terbutaline, but leg blood flow during steady-state exercise increased by approximately 0.5 l/min (P < 0.05). However, at cessation of exercise terbutaline significantly attenuated the rate of fall of [K+]fv at high power from 63 +/- 6 to 38 +/- 6 micromol. l-1.s-1, indicating a reduced reuptake rate of K+. The loss rate of K+ from the leg peaked after around 40 s of exercise, pointing to a rapid activation of reuptake rate of K+. We conclude that, during terbutaline infusion, the reuptake rate of K+ in exercising muscles is attenuated.

Pharmacodynamic modelling of the drug-induced downregulation of a beta 2-adrenoceptor mediated response and lack of restoration of receptor function after a single high dose of prednisone.

Changes in beta 2-adrenoceptor function by chronic dosing of beta 2-mimetics and the possible influence of a single dose of prednisone have been studied as changes over time in the concentration-effect relationship of the beta 2-adrenoceptor agonist terbutaline. Hypokalaemia was used as the specific beta 2-adrenoceptor mediated effect. 8 healthy volunteers were given subcutaneous terbutaline 0.01 mg.kg-1 BW on 3 occasions over a 10-day experimental protocol: 1 Control experiment on Day 1; 2 After 7 days of oral terbutaline 5 mg t.i.d. (Day 8); and 3 After 8 days on oral terbutaline and 12 h after prednisone 100 mg orally (Day 10). The time course of the terbutaline concentrations and hypokalaemia was related using a pharmacokinetic-pharmacodynamic model. A sigmoid and a threshold Emax model were used to relate drug concentrations to effects. The oral terbutaline treatment caused a 35% increase in the distribution volume of SC terbutaline. After one week on oral terbutaline the concentration-effect relationship was shifted to the right and was steeper, with a higher EC50 of terbutaline and higher values for the apparent threshold concentration. These observations are compatible with a decrease in receptor numbers after 7 days of terbutaline in a system characterised by the presence of spare receptors. The data after prednisone pretreatment showed an apparent decline in the baseline plasma potassium concentrations that could be included in the Emax model. There was no change in the concentration-effect relationship 12 hours after prednisone.

Beta-adrenergic mechanisms in the nasal mucosa vascular bed.

In thiopentone-anesthetized mature pigs (n = 7), local intra-arterial infusion of the beta 2-adrenoceptor agonists terbutaline and salbutamol and the beta 3-agonist BRL 37344 induced dose-dependent increases in nasal arterial blood flow (BF) and volume of the nasal mucosa (reflecting capacitance vessel function). Increases were also found in the laser Doppler flowmeter signal, reflecting superficial mucosal BF. In contrast to terbutaline and salbutamol, BRL 37344 showed marked effects on volume. Pretreatment with the beta-adrenoceptor blocker propranolol significantly reduced the vasodilatory effects of terbutaline and salbutamol, whereas the BF increase evoked by BRL 37344 was not affected. Exogenous noradrenaline (NA) induced in vitro dose-dependent contractions of human nasal mucosa biopsies obtained from patients with non-allergic chronic rhinitis (n = 21) or non-allergic nasal polyposis (NANP, n = 16). On a molar basis, the contractile effect of NA was significantly greater in nasal mucosa samples without histological abnormalities when compared to biopsies with abundant inflammatory cells and edema within the submucosa. In the presence of propranolol, the vasoconstrictor effect of NA was significantly enhanced in biopsies with abundant inflammatory cells obtained from patients with NANP (P < 0.01). This observation suggests the possible occurrence of a beta 2 hyper-reactivity in the nasal mucosa of patients with NANP. After precontraction in a Krebs-Ringer solution with 50 nM K+, all nasal biopsies studied showed dose-dependent relaxation to terbutaline, salbutamol and BRL 37344. This relaxant effect was markedly reduced after pretreatment with propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Positive inotropic effects of the beta2-adrenoceptor agonist terbutaline in the human heart: Effects of long-term beta1-adrenoceptor antagonist treatment

Objectives. This study was conducted to determine whether activation of cardiac beta2-adrenoceptors increases contractility in humans and whether this is affected by long-term beta1-adrenoceptor antagonist treatment.Background. Coexistence of beta1- and beta2-adrenoceptors in the human heart is generally accepted. The functional importance of cardiac beta2-adrenoceptors for increases in contractility in humans, however, has not been completely established.Methods. We studied 1) the beta-adrenoceptor subtype mediating positive inotropic effects of the beta2-adrenoceptor agonist terbutaline in vitro (on right atrial and left ventricular preparations from nonfailing human hearts) and increases in contractility (by measurement of systolic time intervals) in vivo in seven healthy male volunteers; and 2) in vivo whether long-term treatment of volunteers with the beta1-adrenoceptor antagonist bisoprolol affects terbutaline-induced increases in contractility.Results. In vitro terbutaline caused a concentration-dependent increase in atrial and ventricular adenylate cyclase activity and force of contraction. Terbutaline effects were antagonized only by the beta2-adrenoceptor antagonist ICI 118,551, indicating that they were mediated by beta2-adrenoceptor stimulation. In vivo intravenous infusions of terbutaline (dose range 25 to 300 ng/kg body weight per min for 15 min) dose dependently increased heart rate and shortened the pre-ejection period and heart rate-corrected electromechanical systole (QS2) time. These effects are mediated predominantly by beta2-adrenoceptor stimulation because they were only marginally affected by the beta1-adrenoceptor antagonist bisoprolol (1 × 10 mg orally), either given 2 h before infusion or long term for 3 weeks.Conclusions. Stimulation of cardiac beta2-adrenoceptors in humans causes not only in vitro but also in vivo positve inotropic effects. Long-term beta1-adrenoceptor antagonist treatment does not considerably affect beta2-adrenoceptor-mediated in vivo increases in contractility. Thus, it may be possible to treat patients with chronic heart failure and long-term beta1-adrenoceptor antagonist therapy with beta2-adrenoceptor agonists if immediate inotropic support is needed.

Influence of β2-Adrenoceptor Stimulation and Glucose on Islet Monoamine Oxidase Activity and Insulin Secretory Response in the Mouse

Changes in the content of monoamines such as dopamine (DA) and serotonin (5-HT) in the insulin granules are known to influence insulin release. The monoamines are inactivated by monoamine oxidase (MAO), a hydrogen peroxide-generating enzyme, which may be of importance for the redox state of the beta-cell. We studied the action of two different insulin secretagogues, the beta 2-adrenoceptor agonist terbutaline and glucose, on islet MAO activity and the plasma levels of insulin and glucose. MAO was assayed with 5-HT, DA, and beta-phenylethylamine as substrates. At 6 min (but not at 2 or 30 min) after terbutaline injection, marked increases of islet MAO activity and the plasma insulin levels were recorded. The plasma glucose levels were of the same magnitude at all time points. Injection of glucose moderately suppressed enzyme activity at 2 min. This occurred concomitantly with the peak increase in plasma levels of insulin and glucose. At 60 min, when the plasma levels of glucose and insulin were restored to basal, a slight increase in MAO activity was observed. At 2 min after injection of different doses of glucose mixed with a maximal dose of terbutaline, the insulin secretory response was either increased (submaximal glucose dose) or unaffected (maximal dose of glucose) by the beta 2-adrenoceptor stimulator. However, when a maximal dose of glucose was given at 6 min after terbutaline, i.e., when islet MAO activity was increased, the insulin response to glucose was suppressed. Starvation for 24 h induced an increase in islet MAO activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired stimulus-evoked mucus secretion in cystic fibrosis bronchi.

Baseline and agonist-stimulated secretion of fucose, hexose, and protein (markers of mucus secretion) was investigated in vitro in 45 bronchial segments from 14 patients with cystic fibrosis (CF) (three after heart-lung transplant, the remainder < 4.5 h after autopsy), in 51 segments from 26 patients with carcinoma (24 resection, 2 after autopsy), and in 4 segments from 3 patients with bronchiectasis (resection). Basal rates of secretion of each mucus marker by CF bronchi were not significantly different from those by carcinoma bronchi bronchiectatic bronchi. However, rates of secretion of each marker in response to the cholinomimetic methacholine (10 microM; n = 11-18, depending on marker) and the beta 2-adrenoceptor agonist terbutaline (10 microM; n = 9-11) were significantly (p < .05) increased in carcinoma bronchi (by 50-117% above basal), but not in CF airways (n = 11-14). The secretory response to the sensory neuropeptide substance P (1 nM to 10 microM; n = 5-7) was also reduced in CF compared with carcinoma bronchi. Physiological and morphological data indicated that the reduced response by CF tissue could not be accounted for by inclusion of autopsy tissue in the study. These data suggest a defect in autonomic control of bronchial secretion in CF, not in the basal rate of secretion, but in its response to receptor stimulation.

Terbutaline-Induced Downregulation of (β2-Adrenoceptors Without Gi-Protein Alterations in Human Lymphocytes

Recent evidence suggests that agonist-induced desensitization of Gs protein-coupled beta-adrenoceptors is accompanied by sensitization of Gi protein-coupled receptors and/or an increase in Gi protein. To find out whether such "cross-regulation" between Gs protein- and Gi protein-coupled receptors can be also demonstrated in vivo in humans, we studied the effects of a 2 week treatment of eight male volunteers with the beta 2-adrenoceptor agonist terbutaline (3 x 5 mg/day) on beta 2-adrenoceptor density and Gi-protein content in lymphocytes and on alpha 2-adrenoceptor density (Gi-coupled receptors) in platelets. Terbutaline decreased the lymphocyte beta 2-adrenoceptor density by about 30%, but had no significant influence on lymphocyte Gi-protein levels (assessed by pertussis toxin-catalyzed [32P]ADP ribosylation) or on platelet alpha 2-adrenoceptor density. We conclude that circulating blood cells are not suitable to demonstrate in humans in vivo a "cross-regulation" between Gs- and Gi-coupled beta- and alpha-adrenoceptors.

Effects of terbutaline and atenolol on large and small airways in asthmatic patients

In order to localize the main site of action of the beta 2-adrenoceptor selective agonist terbutaline and the beta 1-adrenoceptor selective antagonist atenolol in the airways of asthmatic patients, we compared the effects of these drugs on maximal expiratory flow-volume (MEFV) curves when breathing air and when breathing a helium-oxygen (HeO2) mixture. To investigate whether a shift in localization of the bronchodilator effect occurs when terbutaline is inhaled repeatedly, dose-response curves with terbutaline were performed for parameters derived from MEFV curves when breathing air and for density dependence of expiratory airflow. By measurement of MEFV curves when the patients were breathing air alone, it was not possible to determine whether there is a difference in the bronchoconstrictor effect of atenolol between large and small airways. Inhalation of terbutaline to a cumulative dose of 2.0 mg induced a stepwise improvement in expiratory airflow parameters for large and small airways function when breathing air. Doubling the dose of inhaled terbutaline to 4 mg did not result in any further improvement of lung function. Neither atenolol nor terbutaline induced significant mean changes in density dependence of expiratory airflow. This was partly due to large inter- and intra-individual variations of this parameter. Another possibility is that atenolol and terbutaline effect large and small airways function equally.

Galanin and Pancreastatin Inhibit Stimulated Insulin Secretion in the Mouse: Comparison of Effects

The effects of the two intrapancreatic peptides galanin and pancreastatin on basal and stimulated insulin and glucagon secretion in the mouse were compared. It was found that at 2 min after intravenous injection of galanin or pancreastatin (4.0 nmol/kg), basal plasma glucagon and glucose levels were slightly elevated. Galanin was more potent than pancreastatin to elevate basal plasma glucagon levels: they increased from 60 +/- 15 to 145 +/- 19 pg/ml (p less than 0.01) after galanin compared to from 35 +/- 5 to 55 +/- 8 pg/ml (p less than 0.05) after pancreastatin. Plasma insulin levels were lowered by galanin (p less than 0.05), but not by pancreastatin. CCK-8 (6.3 nmol/kg) or terbutaline (3.6 mumol/kg) markedly increased the plasma insulin levels. Galanin (4.0 nmol/kg) completely abolished the insulin response to CCK-8 (p less than 0.001), but pancreastatin (4.0 nmol/kg) was without effect. Galanin inhibited the insulin response to terbutaline by approximately 60% (p less than 0.01), but pancreastatin inhibited the insulin response to terbutaline by approximately 35% only (p less than 0.05). CCK-8 and terbutaline did both elevate plasma glucagon levels by moderate potencies: neither pancreastatin nor galanin could affect these responses. Thus, in the mouse, galanin and pancreastatin both inhibit basal and stimulated insulin secretion, and stimulate basal glucagon secretion. Galanin is thereby more potent than pancreastatin. The study also showed that galanin potently inhibits insulin secretion stimulated by the octapeptide of cholecystokin and by the beta 2-adrenoceptor agonist terbutaline, and that pancreastatin inhibits terbutaline-induced insulin secretion.

Alpha-adrenoceptor blockade by phentolamine inhibits beta-adrenergically and cholinergically induced glucagon secretion in the mouse.

Glucagon secretion is known to be stimulated by activation of the alpha-adrenoceptors. In this study, we investigated whether alpha-adrenoceptor blockade by phentolamine affects basal and stimulated glucagon secretion in the mouse. Phentolamine was injected intraperitoneally to mice at dose levels varying from 2.6 to 260 mumol/kg. It was found that, while decreasing plasma glucose levels, phentolamine did not over this wide dose range affect basal glucagon concentrations indicating an inhibition of the hypoglycaemia-induced glucagon secretion. Further, phentolamine clearly inhibited the glucagon secretory response to beta-adrenergic or cholinergic stimulation. Thus, phentolamine (2.6 mumol/kg), impaired the glucagon secretory response to the beta 2-adrenoceptor agonist terbutaline by 51% (P less than 0.01), and to the cholinergic agonist carbachol by 44% (P less than 0.02). We conclude that alpha-adrenoceptor blockade by phentolamine inhibits the glucagon secretion following hypoglycaemia or stimulation by beta-adrenergic and cholinergic agonists. Thus, the alpha-adrenoceptors seem to be of great importance for glucagon secretion in the mouse.

Studies in vivo and in vitro of terbutaline-induced beta-adrenoceptor desensitization in healthy subjects.

Beta-Adrenoceptor function was studied in eight healthy subjects before, during and 24 and 72 h after cessation of 2 weeks continuous oral treatment with the beta 2-adrenoceptor agonist terbutaline (sustained release, 7.5 mg twice daily). In vivo, blood pressure, heart rate, plasma noradrenaline and plasma cyclic AMP responses to isoprenaline (0.01, 0.02 and 0.05 microgram min-1 kg-1 intravenously) were related to the plasma concentrations of isoprenaline. for comparison, beta 2-adrenoceptor function was evaluated in lymphocytes in vitro by studies of isoprenaline-induced accumulation of cyclic AMP and radioligand binding studies using 125I-iodohydroxybenzylpindolol. In vivo, the beta 2-mediated plasma cyclic AMP response to isoprenaline was markedly attenuated during terbutaline treatment and was still reduced by 38% (P less than 0.05) 72 h after discontinuation of treatment. The blood pressure and heart rate responses to isoprenaline were unaffected by treatment. Isoprenaline-induced elevations of plasma noradrenaline concentrations were markedly reduced during terbutaline treatment. This indicates an attenuation of isoprenaline-induced increases in sympathetic nerve function and could explain why no attenuation of the isoprenaline-induced vasodilatation was observed. Thus, plasma cyclic AMP seems to be a better marker than diastolic blood pressure when evaluating beta 2-adrenoceptor responsiveness in vivo in man, since it is not influenced by counter-regulatory increases in sympathetic nerve activity and/or noradrenaline overflow from sympathetic nerves. In lymphocytes, the isoprenaline-stimulated cyclic AMP accumulation was reduced by 75% and the beta-adrenoceptor binding sites were reduced by 40% 12 h after dosing. Also the lymphocyte beta 2-adrenoceptors recovered slowly after withdrawal of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of alpha-adrenoceptor blockade by phentolamine on basal and stimulated insulin secretion in the mouse.

The sympathetic nervous system is known to innervate the pancreatic islets and to have the capability to influence islet hormone release. The effects are, however, complex since the islet nerves contain catecholaminergic as well as peptidergic fibres, and the catecholamines stimulate alpha- as well as beta-adrenoceptors. The present study was undertaken to establish the possible influence of the alpha-adrenoceptors on basal and stimulated insulin secretion under in vivo conditions. The alpha-adrenoceptor blocker phentolamine was injected at various dose levels i.p. to mice and a dose-dependent increase in plasma concentrations of insulin was seen. The maximal plasma insulin levels were observed 10 min after injection and were accompanied by decreased plasma glucose concentrations. Additionally, plasma glucose levels fell in response to phentolamine by an apparent insulin-independent manner, since at the low dose of 2.6 mumol kg-1, plasma glucose levels did decrease without any apparent increase in plasma insulin levels. After injection of a low dose of phentolamine 10 min prior to a rapid i.v. injection of one of four different insulin secretagogues, the following effects on insulin release were observed. Glucose (+55%) and the cholinergic agonist carbachol (+140%) displayed a potentiated insulin secretory response after phentolamine pretreatment, whereas the beta 2-adrenoceptor agonist terbutaline (-45%) had a blunted, though not abolished, insulin response. The absolute insulin secretory response to CCK-8 was unaffected by phentolamine despite the fact that plasma glucose levels were lowered by phentolamine. In conclusion, phentolamine enhanced insulin secretion and depressed plasma glucose levels in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Actions of bronchodilator drugs, glucocorticoid, and their combinations on airways in rats and guinea pigs

The principal aim of the present investigation was to examine in detail individual and combined actions on airways of four antiasthmatic drugs with different mechanisms of action. They were theophylline (THEO), the beta 2-adrenoceptor agonist terbutaline (TER), the antimuscarinic ipratropium bromide (IPRA), and the glucocorticoid betamethasone (BM). The respiratory measurements (intratracheal pressure in rats and lung resistance and dynamic lung compliance in guinea pigs) were performed in anaesthetized, mechanically ventilated animals. Mild, moderate, and submaximal obstruction of mainly large or small airways were induced by a cumulative administration of either methacholine (MeCh) or leukotriene D4 (LTD4), both i.v. The antiasthmatic drugs were given acutely i.v., but THEO and BM also as intraperitoneal pretreatments. Moreover, actions of the antiasthmatic drugs were studied ex vivo on lung beta-adrenoceptors in rats and guinea pigs. 3H-dihydroalprenolol was used as a ligand in the beta-receptor binding assay. A detailed evaluation of the lung resistance and dynamic lung compliance responses to MeCh and LTD4 suggested that MeCh induced obstruction in more proximal airways than LTD4. THEO attenuated both airway challenges, being about 2-4 times more efficient on LTD4 than on MeCh. TER inhibited both MeCh- and LTD4-induced airway obstruction about equally, whereas IPRA was effective on the MeCh-induced obstruction only. In most cases, treatment with THEO+TER or THEO+IPRA attenuated the MeCh-induced mild or moderate obstruction of large airways additively, and the submaximal airway response to MeCh synergistically. The relatively good effect of THEO on small airway obstruction caused by MeCh was not augmented by TER or IPRA. In contrast to these results, combination of subefficient doses of THEO and TER, but not of THEO and IPRA, resulted in an antagonistic interaction on the MeCh challenge in rats and guinea pigs. The combined action of THEO+TER was at its best additive on large and small airways obstruction caused by LTD4. Addition of IPRA to THEO treatment did not modify the effects on LTD4 challenge. Neither TER nor IPRA enhanced the cardiovascular effects of THEO in rats or guinea pigs. THEO administration to rats and guinea pigs resulted in plasma concentrations (7.5-32 micrograms/ml) that were roughly comparable to clinically relevant values. The respective lung tissue concentrations were 53-81% of the plasma values. In rats, but not in guinea pigs, combined treatment with THEO+TER increased the THEO concentration in lung tissue.(ABSTRACT TRUNCATED AT 400 WORDS)