Paradoxal effect of salbutamol in an in vitro model of bronchoprotection

Salbutamol-induced hyperresponsiveness to acetylcholine was investigated in human and guinea-pig isolated airways and cultured human airway smooth muscle cells. Salbutamol (10 -7 -10 -5 M) inhibited contractions induced by low concentrations of acetylcholine (10 -8 -10 -7 M) but potentiated contractions induced by higher concentrations of acetylcholine (10 -5 -10 -3 M). Pretreatment with the calcium channel antagonist nicardipine suppressed salbutamol-induced hyperresponse. Stimulation of cultured human airway smooth muscle cells with salbutamol (10 -6 M) amplified intracellular calcium concentration rise induced by acetylcholine (10 -5 M). Propranolol (10 -7 M), a β 1 - and β 2 -adrenoceptor antagonist, and ICI 118551 (10 -7 -10 -6 M), a β 2 -adrenoceptor antagonist, suppressed the inhibitory effect of salbutamol but did not inhibit the hyperresponse on high concentrations of acetylcholine. In contrast, higher concentration of propranolol (10 -6 M) inhibited salbutamol-induced hyperreactivity. Effects of salbutamol were not affected by atenolol, a β 1 -adrenoceptor blocker. Salbutamol-induced hyperresponsiveness is mediated through a mechanism involving calcium channel activation.