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

Abstract

1 Salmeterol, a novel, long-acting /J-adrenoceptor agonist, has been compared with isoprenaline and salbutamol for activity in vitro on a range of f-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)F2. or electrical stimulation) and human bronchus (contracted by PGF2a) 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 sahueterol persisted for periods of up to 12h, despite continuous superfusion with agonist-free medium. However, these persistent responses were rapidly and fully reversed by the fl-adrenoceptor blocking drug, propranolol (O.1juM). 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 /i-adrenoceptor blocking drug, sotalol (10pM), 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 fJ,-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 72#M, salmeterol exhibited weak antagonism of isoprenaline-induced increases in atrial force of contraction. This antagonism was less marked than that caused by salbutamol (42 pM). 6 On the guinea-pig isolated gastric fundus strip, a putative /3-adrenoceptor containing preparation, salbutamol and salmeterol had only modest agonist activity, being 20-30 fold less potent than isoprenaline and the selective ,3-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 90min, 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 12-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 inha...

Pharmacological Characterization of Abediterol, a Novel Inhaled β2-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models

“…There was a trend toward higher selectivity for abediterol and salmeterol than for formoterol and indacaterol; the comparison between abediterol and salmeterol selectivity ratios was difficult because of the low ␤ 1 efficacy observed for both compounds in guinea pig atria. Our results are consistent with those reported previously, indicating that the ␤ 1 /␤ 2 and ␤ 3 /␤ 2 selectivity ratios of formoterol and indacaterol are inferior to those of salmeterol (Ball et al, 1991;Battram et al, 2006;Bouyssou et al, 2010). In humans, it has been reported that activity at the ␤ 1 -adrenoceptor might be responsible for some of the cardiac side effects associated with ␤-adrenergic agonism (Levine and Leenen, 1989).…”

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

“…Interestingly, the strips relaxed again very soon after removal of the antagonist. However, this recovery, which is denoted 'reassertion', occurs repeatedly after successive challenges with the antagonist [28][29][30]. Although other interpretations have also been suggested [25] (see also below), the diffusion Figure 1 'Microkinetic' model.…”

G Protein–Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands

“…Sal has a long duration of action at the b2-AR that persists extensive washout of antagonist (Ball et al, 1991;Green et al, 1996). Therefore, it seemed plausible that Iso and Sal could differ in the duration of gene expression upregulation.…”