Salmeterol, a novel, long‐acting β2‐adrenoceptor agonist: characterization of pharmacological activity in vitro and in vivo

Abstract

1 Salmeterol, a novel, long-acting β-adrenoceptor agonist, has been compared with isoprenaline and salbutamol for activity in vitro on a range of β-adrenoceptor containing preparations from laboratory animals and man, and in vivo for bronchodilator activity in the conscious guinea-pig. 2 Salmeterol, like isoprenaline and salbutamol, relaxed preparations of both guinea-pig trachea (contracted by prostaglandin (PG)F_2α or electrical stimulation) and human bronchus (contracted by PGF_2α) in a concentration-related fashion. Salmeterol was of similar potency to isoprenaline and more potent than salbutamol on both airway preparations. 3 Relaxant responses of superfused guinea-pig trachea and human bronchus to isoprenaline and salbutamol declined rapidly when the agonists were washed from the tissues, with complete recovery within 10 min, whereas responses to salmeterol were more persistent. In electrically-stimulated guinea-pig trachea preparations, inhibition by salmeterol persisted for periods of up to 12 h, despite continuous superfusion with agonist-free medium. However, these persistent responses were rapidly and fully reversed by the β-adrenoceptor blocking drug, propranolol (0.1 μm). In further studies, on guinea-pig trachea, propranolol caused concentration-related parallel, rightward shifts of salmeterol concentration-effect curves, yielding a pA₂ of 9.0. The slope of the Schild plot was 1.02. 4 Another β-adrenoceptor blocking drug, sotalol (10 μm), also fully and rapidly reversed established submaximal responses to salmeterol in superfused guinea-pig trachea. However, after administration of sotalol was stopped, the antagonism waned, and salmeterol responses were reasserted without the addition of further agonist. 5 In the β₁-adrenoceptor containing preparation, rat left atria, isoprenaline exhibited potent, concentration-related, positive inotropic activity, whereas salbutamol and salmeterol were at least 2000–5000 fold less potent, and appeared to be partial agonists. At a concentration of 72μm, salmeterol exhibited weak antagonism of isoprenaline-induced increases in atrial force of contraction. This antagonism was less marked than that caused by salbutamol (42 μm). 6 On the guinea-pig isolated gastric fundus strip, a putative β₃-adrenoceptor containing preparation, salbutamol and salmeterol had only modest agonist activity, being 20–30 fold less potent than isoprenaline and the selective β₃-adrenoceptor agonist, BRL 35135. 7 In conscious guinea-pigs, inhaled salmeterol and salbutamol were approximately equipotent in causing dose-related bronchodilatation. Whereas the duration of action of salbutamol at its threshold-effective dose was less than 90 min, the responses to a similarly effective dose of salmeterol were well-maintained for at least 6 h. 8 Salmeterol is therefore a potent and selective β₂-adrenoceptor agonist with a remarkably long duration of action in isolated superfused airways smooth muscle. It also causes persistent bronchodilatation in vivo, in the guinea-pig, when administered by the inhaled route.