Evaluation of the beta(2) adrenoceptor agonist antagonist activity of formoterol and salmeterol

Background - Salmeterol and formoterol have a lower intrinsic activity at beta(2) receptors than isoprenaline in human bronchus in vitro. The aim of the present study was to evaluate in vivo the beta(2) agonist/antagonist activity of salmeterol and formoterol at rest with low endogenous adrenergic tone, on exercise with raised endogenous adrenergic tone, and in the presence of fenoterol, an exogenous full beta(2) receptor agonist. Methods - Eight normal subjects were randomised to receive single doses of placebo, salmeterol 300 mu g, formoterol 72 mu g, or propranolol 80 mg at weekly intervals. beta(2) adrenoceptor responses were evaluated at rest, at peak exercise, and after treatment with fenoterol 2.4 mg. Results - At rest salmeterol and formoterol exhibited equivalent beta(2) agonist activity with regard to decrease in serum potassium levels and increase in finger tremor, with propranolol having no effect. Salmeterol and formoterol, like propranolol, potentiated the hyperkalaemic delta response to exercise compared with placebo, consistent with beta(2) antagonism: (mean difference and 95% confidence interval (CI) compared with placebo) salmeterol 0.20 (0.02 to 0.38) mmol/l, formoterol 0.17 (0.00 to 0.34) mmol/l, propranolol 0.45 (0.08 to 0.82) mmol/l. Propranolol blunted the heart rate delta response to exercise, consistent with beta(1) blockade, whilst salmeterol and formoterol had no effect. Salmeterol and formoterol, like propranolol, attenuated the hypokalaemic, tremor, and heart rate delta responses to fenoterol compared with placebo, in keeping with beta(2) blockade: potassium, salmeterol 0.18 (0.0 to 0.36) mmol/l, formoterol 0.17 (-0.03 to 0.37) mmol/l, propranolol 0.80 (0.54 to 1.06) mmol/l; tremor, salmeterol -0.69 (-1.26 to -0.12) log units, formoterol -0.71 (-1.53 to 0.11) log units, propranolol -0.85 (-1.66 to -0.04) log units; heart rate, salmeterol -6 (-13 to 1) beats/min, formoterol -10 (-19 to -1) beats/min, propranolol -18 (-29 to -7) beats/min. Conclusions - At rest with low endogenous adrenergic tone salmeterol and formoterol showed equivalent beta(2) mediated agonist activity in terms of serum potassium and finger tremor responses. In the presence of raised endogenous adrenergic tone at peak exercise and in the presence of fenoterol(an exogenous full beta(2) receptor agonist), salmeterol and formoterol, like propranolol, exhibited beta(2) receptor antagonism as evidenced by their attenuation of beta(2) receptor mediated responses. The degree of beta(2) blockade with formoterol and salmeterol was comparable but less than with propranolol. The relevance of these findings at extrapulmonary beta(2) receptors with regard to airway beta(2) responses remains unclear and warrants further investigation.