EXPRESSION OF THE BETA(2) ADRENOCEPTOR PARTIAL AGONIST/ANTAGONIST ACTIVITY OF SALBUTAMOL IN STATES OF LOW AND HIGH ADRENERGIC TONE

Background - Salbutamol exhibits partial agonist/antagonist activity at airway beta(2) receptors in vitro in that it attenuates the bronchorelaxant effect of the full agonist isoprenaline. The aim of the present study was to characterise the partial beta(2) agonist/ antagonist activity of salbutamol in vivo during supine rest and exercise, in states of low and high adrenergic tone. Methods - Eight normal subjects were randomised to receive single oral doses of salbutamol 2 mg, 4 mg, 8 mg (S-2, S-4, S-8), placebo (PL), or propranolol 80 mg (PR). The beta(2) adrenoceptor responses were evaluated after supine rest and subsequently in response to maximal exercise. Results - Salbutamol demonstrated a dose-related increase in resting heart rate and tremor and a fall in serum potassium level consistent with beta(2) agonism. On exercise, the hyperkalaemic response was augmented by propranolol compared with placebo consistent with beta(2) blockade: mean difference for delta response (95% CI) PR v PL was 0.60 (0.02 to 1.27) mmol/l. This effect also occurred with salbutamol in a dose-related fashion: S-8 v PL 0.33 (0.01 to 0.71) mmol/l, S-8 v S-2 0.31 (-0.02 to 0.61) mmol/l. Whilst propranolol blunted exercise heart rate in keeping with beta(1) blockade, salbutamol had no effect. Exercise produced an increase in lymphocyte beta(2) receptor binding density (Bmax) which was not affected by salbutamol. Plasma levels of adrenaline and noradrenaline at peak exercise were also unaltered by salbutamol in comparison with placebo. Conclusions - In a state of low adrenergic tone at rest salbutamol produces effects consistent with beta(2) agonism. In contrast, in a state of increased adrenergic tone during exercise salbutamol produced beta(2) selective antagonism as evidenced by its effects on exercise-induced hyperkalaemia (beta(2)) but not on exercise-induced tachycardia (beta(1)). The effects of salbutamol on beta(2) receptor density do not explain its effects on exercise-induced hyperkalaemia since upregulation rather than downregulation was observed. This in vivo phenomenon of partial beta(2) agonist/antagonist activity of salbutamol may be of relevance in the setting of acute asthma if adrenergic tone is increased.