Comparison of the effects of selective and non-selective beta-adrenoreceptor agonists on the pro-inflammatory activities of human neutrophils in vitro

The objective of this study was to measure and compare the effects of 4 sel ective (fenoterol, formoterol, salbutamol, salmeterol) and 3 non-selective (epinephrine, norepinephrine, isoproterenol), beta-adrenoreceptor agonists, at a fixed, final concentration of 1 mu M, on intracellular cyclic AMP lev els in human neutrophils in vitro and to relate alterations in these to the effects of the test agents on the production of superoxide and release of elastase following activation of the cells with the chemoattractant, FMLP. Intracellular cAMP was measured by radioimmunoassay, while superoxide and e lastase were assayed using lucigenin-enhanced chemiluminescence and colorim etric procedures respectively. Of the 7 agents tested, fenoterol, formotero l, epinephrine and isoproterenol caused a substantial increase in neutrophi l cAMP levels, which correlated well with the inhibitory effects of these a gents on superoxide production and elastase release. The other agents were either inactive (salmeterol), or weakly active (norepinephrine, salbutamol) . Pretreatment of neutrophils with the non-selective beta-adrenoreceptor bl ockading agent, propranolol (2 mu M), attenuated the cAMP-mediated, anti-in flammatory interactions of formoterol, epinephrine and isoproterenol with n eutrophils, while atenolol, a selective beta(1)-blockading agent, as well a s alpha(1)- and alpha(2)-adrenoreceptor antagonists were ineffective. These findings demonstrate that some, but not all, currently used beta-agonists suppress the proinflammatory activity of human neutrophils through interact ion with beta(2)-adrenoreceptors on these cells and activation of adenylyl cyclase. If operative in vivo, these anti-inflammatory properties may contr ibute, albeit in a secondary manner, to the therapeutic activity of fenoter ol, formoterol, epinephrine and isoproterenol.