Estimation of the efficacy and affinity of the β₂‐adrenoceptor agonist salmeterol in guinea‐pig trachea

Abstract

1 We have attempted to estimate the affinity and efficacy of the new fl2-adrenoceptor agonist salmeterol in the guinea-pig isolated trachea and to compare these estimates with those obtained for salbutamol. 2 The kinetics of the relaxation to salmeterol were considerably slower than those to salbutamol and the responses were poorly defined. Nevertheless, in experiments employing a cumulative curve design both salmeterol and salbutamol exhibited partial agonist behaviour. Operational model-fitting of these data indicated that the intrinsic efficacies of the two agonists were indistinguishable but that salmeterol had an affinity (pKA = 7.4) some 30 fold greater than salbutamol (pKA = 5.9). 3 Single dose experiments, using maximally effective concentrations of salmeterol or salbutamol were carried out in an attempt to quantify more reliably the relative efficacies of the two agonists. In these experiments salbutamol was found to have an efficacy (2.5) approximately 3 fold greater than that of salmeterol (0.8). 4 Full/partial agonist interaction studies were carried out to provide another estimate of the affinity of salmeterol. Isoprenaline and adrenaline were employed as full agonists in these experiments and the affinity (pKB) estimates obtained for salmeterol against these agonists were 7.3 and 7.4 respectively. These affinity estimates were similar to the pKA value (7.4) obtained by operational model-fitting. 5 Salmeterol has slightly lower efficacy (3 fold) but markedly greater affinity (30 fold) than salbutamol at fl2-receptors. The slightly lower efficacy of salmeterol is unlikely to have clinical implications for this drug as a bronchodilator f62-adrenoceptor agonist in asthma.

Effects of formoterol, salmeterol or oxitropium bromide on airway responses to salbutamol in COPD

“…In fact, DOUGALL et al [17], using adrenaline and isoprenaline as agonists, noted significantly less steep concentration-effect curves in the presence of salmeterol as compared to control curves. More, recently, NALINE et al [18] showed that when isolated human bronchi were incubated in the presence of formoterol, a significant (1 log unit) displacement of the concentration-response curves to adrenaline was observed with long acting β 2 -agonist at a concentration giving a maximal effect.…”

β‐Adrenoceptor subtypes and the opening of plasmalemmal K+‐channels in bovine trachealis muscle: studies of mechanical activity and ion fluxes

“…The present findings concerning the effects of salmeterol on 86Rb+ efflux, parallel the electrophysiological observations (Cook et al, 1993) in guinea-pig trachealis that salmeterol itself fails to cause cellular hyperpolarization but can inhibit the hyperpolarization induced by isoprenaline. We suggest that the weakness of the effects of salmeterol on 86Rb+ efflux from trachealis muscle and on membrane potential, combined with its ability to antagonize a full agonist, may be explicable in terms of its reported (Dougall et al, 1991) low intrinsic efficacy at P2-adrenoceptors.…”

“…These observations provide very strong evidence to suggest that, in contrast to isoprenaline, procaterol and salbutamol, salmeterol is ineffective in provoking the opening of plasmalemmal K+-channels in trachealis muscle. Studies of guinea-pig trachealis pre-contracted with carbachol (Ball et al, 1991;Dougall et al, 1991;Waldeck & Kallstrom, 1991;Cook et al, 1993) have indicated that salmeterol is a partial rather than a full agonist at P2-adrenoceptors. The partial agonist activity of salmeterol was not revealed by comparing the maximal relaxant effects of isoprenaline and salmeterol in histamineprecontracted bovine trachealis (Figure 1 and 2).…”

“…In order to shed more light on (a) the identity of the P-adrenoceptor subtype mediating K+-channel opening, (b) the importance of K+-channel opening to the mechanoinhibitory effects of agonists at P-adrenoceptors and (c) the pharmacological properties of salmeterol (Ball et al, 1991;Dougall et al, 1991), we studied mechanical and electAuthor for correspondence.…”

“…That such K+-channel opening is mediated by the activation of P-adrenoceptors is indicated by the ability of propranolol to inhibit the hyperpolarization of airways smooth muscle induced by isoprenaline (Ito & Tajima, 1982;Allen et al, 1985;Honda et al, 1986). However, since propranolol has approximately equal affinity for Pl-and P2-adrenoceptors, this agent does not help in the identification of the P-adrenoceptor subtype responsible for promoting the K+-channel opening.In order to shed more light on (a) the identity of the P-adrenoceptor subtype mediating K+-channel opening, (b) the importance of K+-channel opening to the mechanoinhibitory effects of agonists at P-adrenoceptors and (c) the pharmacological properties of salmeterol (Ball et al, 1991;Dougall et al, 1991), we studied mechanical and electAuthor for correspondence.rophysiological changes in guinea-pig isolated trachealis (Cook et al, 1993). In these studies of guinea-pig trachealis, the membrane hyperpolarization induced by agonists at Padrenoceptors was used as an index of plasmalemmal K+-channel opening.…”