1. Adrenoceptor subtype function was studied in isolated adipocytes obtained by subcutaneous fat biopsies from nine patients with mild asthma. The biopsies were taken before and after 7 days treatment with 25 mg of prednisolone given orally. Lipolytic activity after stimulation with various adrenergic agents was measured, using glycerol release as an index of lipolysis. The number of β 1 - and β 2 -adrenoceptor binding sites was determined in radioligand binding experiments and β 1 - and β2-adrenoceptor mRNA levels were measured with a solution hybridization assay. 2. Lipolytic sensitivity (ED 50 ) to isoprenaline, a nonselective β-adrenoceptor agonist, increased 50-fold after treatment ( P = 0.04). Sensitivity to terbutaline, a selective β 2 -adrenoceptor agonist, increased 25-fold ( P =0.01), whereas the ED 50 values for dobutamine, a selective β 1 -adrenoceptor agonist, did not change significantly. Likewise, the sensitivity to the α 2 -adrenoceptor agonist, clonidine, and to the drugs acting at post-receptor levels did not change significantly. Basal and maximum lipolytic rates on stimulation were not altered by the treatment. 3. The number of β 2 -adrenoceptor binding sites increased by 60% after treatment ( P <0.05), whereas the β 1 -adrenoceptor binding sites were not affected. The affinity of each receptor subtype for the displacing ligand, ICI 118.551, was not significantly altered by steroids. No significant changes were demonstrated in either β 1 - or β 2 -adrenoceptor mRNA levels. 4. Thus, glucocorticoids selectively increase β 2 -adrenoceptor density and function in patients with asthma, studied by using subcutaneous fat cells as an experimental model.

1. To investigate the effects of acute β 1 -adrenoceptor blockade on sympathetic nervous activity, cardiac and whole-body noradrenaline kinetics were determined during intravenous infusions of saline placebo and of metoprolol (10-15 mg plus 150 μg min −1 kg −1 ) in 10 patients undergoing diagnostic cardiac catheterization, in whom β-adrenoceptor antagonists had been discontinued for 7 days. 2. Coronary haemodynamics were measured in these 10 patients plus two others. Compared with saline placebo, metoprolol administration was associated with decreases in heart rate (68 ± 2 to 59 ± 3 beats/min, P < 0.001) and coronary sinus blood flow (86 ± 8 to 68 ± 6 ml/min, P < 0.001) and an increase in calculated coronary vascular resistance (1.42 ± 0.19 to 1.75 ± 0.22 mmHg min ml −1 , P < 0.001). Arterial and femoral venous noradrenaline concentrations, whole-body noradrenaline clearance and whole-body noradrenaline spillover to arterial plasma did not change. In contrast, cardiac noradrenaline spillover (33.7 ± 5.1 to 20.2 ± 4.3 pmol/min, P < 0.05) and cardiac noradrenaline clearance (31 ± 3 to 23 ± 3 ml/min, P < 0.001) were significantly decreased during metoprolol administration. 3. These results may be explained by inhibition of pre-junctional facilitatory β-adrenoceptors, which we hypothesize may be predominantly of the β 1 -subtype in the heart and of the β 2 -subtype in the periphery.

1. To investigate the possible role of adrenaline as a modulator of noradrenaline release from the sympathetic nervous system, the responses of cardiac and whole-body noradrenaline kinetics to intravenous infusions of adrenaline (30 ng min −1 kg −1 ) and matching saline placebo were determined at rest and during supine bicycle exercise in 16 patients undergoing cardiac catheterization, in whom β-adrenoceptor antagonists had been discontinued for 72 h. 2. At rest and compared with placebo, infusion of adrenaline was associated with a small increase in arterial plasma noradrenaline from 211 ± 129 pg/ml to 245 ± 29 pg/ml ( P < 0.05). Increases in whole-body noradrenaline spillover to arterial plasma were larger (from 282 ± 40 ng min −1 m −2 to 358 ± 41 ng min −1 m −2 , P < 0.01) and there was a trend towards an increase in whole-body noradrenaline clearance. Cardiac noradrenaline clearance was modestly increased during adrenaline infusion, but cardiac noradrenaline spillover was not altered despite increases in heart rate and coronary sinus plasma flow. Adrenaline infusion was associated with symptomatic myocardial ischaemia in four of 14 patients with coronary heart disease. 3. Supine bicycle exercise was associated with significant increases in peripheral noradrenaline concentrations and in cardiac and whole-body noradrenaline spillover. The increases on exercise were not significantly different for these variables during saline and adrenaline infusions. 4. Infusion of adrenaline to produce ‘physiological’ increases in plasma adrenaline concentration was associated with an increase in total noradrenaline release, as assessed by whole-body noradrenaline spillover to plasma. This is consistent with the hypothesis that adrenaline may modulate noradrenaline release by acting upon pre-junctional β-adrenoceptors, but could also be explained by reflexogenic responses to the haemodynamic effects of adrenaline.

1. Maximal binding capacity ( B max. ) and the dissociation constant ( K D ) for the β-adrenoceptor antagonist 125 I-cyanopindol were estimated in membrane preparations of hilar, lobar/main bronchi (level 1) and peripheral lung (level 11) of grossly normal lungs resected for bronchial carcinoma. The tissue distribution of 125 I-cyanopindol-binding sites was assessed by autoradiography of complementary cryostat sections. The data obtained from the resections for carcinoma and bronchiectasis were used as disease controls for comparison with those obtained from patients with cystic fibrosis and asthma. 2. In carcinoma controls, mean B max. values (± sem ) for airway levels 1 and 11 were 89 ± 4 and 133 ± 6 fmol/mg of protein, respectively ( P <0.01). The corresponding K D values at each airway level were similar, i.e. 29 ± 2 and 33 ± 1 pmol/l, respectively. Autoradiography revealed that there was dense labelling of bronchial and bronchiolar epithelium and most strikingly of the alveolar wall. 3. Compared with carcinoma controls, mean B max. values in cystic fibrosis were significantly reduced in membrane preparations of both airway levels 1 and 11 ( P <0.01). Autoradiography showed the reduction was most apparent in alveolar wall and bronchial epithelium. 4. There was a tendency to reduction of B max. in membrane preparations from patients with bronchiectasis at airway level I, but this failed to reach statistical significance. Autoradiography demonstrated that the density of labelling was significantly reduced in bronchial epithelium and bronchial smooth muscle as compared with carcinoma controls ( P <0.01). 5. The B max. values were not significantly altered in membranes prepared from both airway levels in asthma, albeit there was a tendency towards reduction in B max. at level 1. At this level autoradiography demonstrated significantly reduced labelling of bronchial epithelium ( P >0.01) and submucosal glands ( P >0.05) but not of bronchial smooth muscle. 6. It is most likely that the reduction in β-adrenoceptor number that we have found in cystic fibrosis is secondary to pulmonary infection and airway inflammation. Its relationship to the primary defect remains unclear.

1. Hypokalaemia may be produced in man by intravenous adrenaline infusion, or as a result of pathological disturbances which have led to a high plasma adrenaline concentration. 2. With isolated human leucocytes used as a cellular model, adrenaline at concentrations at and above 9 nmol/l increases the influx of rubidium (a model for potassium flux) into cells, with a simultaneous efflux of sodium. There is no effect on Na + , K + -ATPase activity in lysed leucocytes. 3. Use of the adrenoceptor blockers timolol and atenolol shows that the demonstrated effect of adrenaline on coupled active transport of ions is mediated by β 2 -adrenoceptors.

1. To determine whether circadian variation in adrenoceptor function might underlie the ‘morning dip’ in peak expiratory flow (PEF) rate and its abolition by salbutamol we measured indices of β-adrenoceptor function (B max. and K d ), the ratio FEV 1 /FVC, and plasma cortisol at 08.00 and 18.00 hours on and off salbutamol (4 mg given orally every 4 h) in five extrinsic asthmatic patients and five normal volunteers. 2. There was a significant circadian variation in receptor numbers (B max. ) in both the control and asthmatic groups which was not abolished on treatment with salbutamol. 3. Both groups appeared to compensate for loss of receptor number induced by salbutamol administration by increasing receptor affinity. 4. For comparable combinations of drug/time, there was no significant difference between the control and asthmatic groups. 5. We conclude that the ‘morning dip’ observed in asthmatic patients cannot simply be explained by changes in cell receptor number or affinity, as our results suggest that both groups have intact β-adrenoceptor function. Nevertheless, our observations of the normal circadian rhythm has important implications for future studies of β-adrenoceptors in asthmatic patients.

1. To determine whether circadian variations in adrenergic responsiveness might underlie nocturnal wheezing in asthma, we measured cardiovascular, airway and plasma adenosine 3′:5′-cyclic monophosphate (cyclic AMP) responses to stepwise infusions of l -adrenaline (0.01, 0.03 and 0.075 μg min −1 kg −1 ) at 4 h intervals over 24 h in five extrinsic asthmatic men. 2. Peak expiratory flow, blood pressure, heart rate and plasma cyclic AMP showed a significant circadian variation with peak values at 16.00 hours and trough values at 04.00 hours. 3. The β 2 -adrenoceptor-mediated increases in peak flow and cyclic AMP were similar at all times, but adrenergic responsiveness (measured by response/log dose of infused adrenaline) was greater at 04.00 hours than at 16.00 hours because of the lower baseline values at night. 4. Blood pressure and heart rate responses to adrenaline infusions did not significantly differ over 24 h. 5. Airway responses to inhaled adrenaline were studied on the second day; the mean peak flow after adrenaline was similar at 16.00 hours to that at 04.00 hours and since the pretreatment values were lower at 04.00 hours, the magnitude of response to inhaled adrenaline was greater at night. 6. We conclude that there is no significant circadian change in adrenergic responses in asthma and that adrenoreceptor dysfunction is not important in the pathogenesis of nocturnal asthma.

1. Responsiveness of the β-adrenoceptor adenylate cyclase system was measured in lymphocytes from healthy young and old subjects by incubating the cells with isoprenaline in the presence of a phosphodiesterase inhibitor and by measuring production of adenosine 3′:5′-cyclic monophosphate (cyclic AMP) with a competitive binding assay. 2. The two groups did not differ significantly in the levels of cyclic AMP produced or in the concentration of isoprenaline required to give half-maximal stimulation of the cells (ED 50 ).

1. Changes in forearm blood flow to intra-arterial infusion of isoprenaline and the chronotropic response to intravenous boluses of isoprenaline were measured in 15 healthy volunteer subjects, eight younger than 25 years and seven older than 50 years. Intra-arterial blood pressure and basal plasma renin activity, adrenaline and noradrenaline were also measured. 2. Young subjects exhibited a greater increase in forearm blood flow than old subjects, to all four doses of isoprenaline used, a greater cardiac isoprenaline responsiveness (measured by the increase in heart rate; P <0.001) and a higher renin ( P <0.02). 3. Resting values of blood pressure, forearm blood flow, adrenaline and noradrenaline were not significantly different in young and old subjects. In the latter, noradrenaline correlated with forearm blood flow ( r = −0.77, P <0.05), forearm vascular resistance ( r = 0.86, P <0.02) and mean arterial pressure ( r = 0.83, P <0.02), whereas in the younger subjects forearm blood flow was related to adrenaline ( r = 0.78, P <0.05). 4. These data provide evidence for an age-related parallel reduction in cardiac, peripheral vascular and renal β-adrenoceptor-mediated responses.