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 (S2, S4, S8), 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: S8 v PL 0.33 (0.01 to 0.71) mmol/l, S8 v S2 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.