Abstract
The mechanisms producing long duration of action for formoterol and salmeterol are not fully understood. The aim of the current study was to examine how the concentration of long and short acting β2-adrenoceptor agonists affects their relaxation kinetics in airway smooth muscle. Onset (time to peak relaxation) and offset of action (reassertion of reversible relaxation following repeated β-adrenoceptor blockade and washout) were measured in the guinea pig trachea precontracted postjunctionally by carbachol 0.3 μM in vitro. At 10−1,000% (C 1O−C 1,000) of the maximally effective concentration (C 100: 150 nM formoterol, 10 μM salbutamol, 30 μM salmeterol), salbutamol had a shorter time to peak relaxation than did salmeterol. Formoterol and salmeterol had a similar time to peak relaxation at C 10, but, in contrast to salmeterol, formoterol's time to peak relaxation became markedly shorter and similar to that of salbutamol as the concentration was increased up to C 1,000. Significant reversible reasserted relaxation was demonstrated for salmeterol alone at C 10. At C 30−C 1,000, however, salmeterol produced irreversible relaxation only, in spite of repeated β-adrenoceptor blockade by sotalol 10 μM followed by washout. In contrast, formoterol produced an increasing reversible reasserted relaxation at C 30−C 1,000. Salbutamol produced significant, reversible reasserted relaxation at C 1,000 only. In conclusion, the concentration determines the onset and offset of action for formoterol and to a lesser extent for salbutamol, but not for salmeterol. To cause sustained action, a submaximally effective concentration is sufficient for salmeterol, whereas formoterol requires a maximally effective concentration. The rank order of concentration dependence for the relaxation kinetics is not paralleled by the rank order of lipophilicity for formoterol, salbutamol, and salmeterol. Therefore, factors other than lipophilicity may also play a role in determining the relationship between concentration and relaxation kinetics for the investigated β2-agonists.
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Anderson, P., Lötvall, J. & Linden, A. Relaxation kinetics of formoterol and salmeterol in the guinea pig trachea in vitro. Lung 174, 159–170 (1996). https://doi.org/10.1007/BF00173308
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DOI: https://doi.org/10.1007/BF00173308