EFFECTS OF ENANTIOMERS OF BETA(2)-AGONISTS ON ACH RELEASE AND SMOOTH-MUSCLE CONTRACTION IN THE TRACHEA

The beta(2)-agonists currently used as bronchodilators are racemic mix tures of R- and S-enantiomers. In the present study, we examined the e ffects of enantiomers of the Pz-agonists albuterol and formoterol on a cetylcholine (ACh) release from equine trachealis parasympathetic nerv es. ACh release was evoked by electrical field stimulation (20 V, 0.5 ms, 0.5 Hz) and measured by high-performance liquid chromatography cou pled with electrochemical detection. We also tested the effects of ena ntiomers of albuterol and formoterol on equine tracheal smooth muscle (TSM) contraction in response to exogenous ACh. R- and RS-albuterol (1 0(-8) to 10(-5) M) and RR- and RR/SS-formoterol (10(-8) to 10(-5) M) a ugmented ACh release in a concentration-dependent manner. Beginning at 10(-6) M, SS-formoterol significantly increased ACh release, and at 1 0(-5) M, release increased by 71.9 +/- 8.7% over baseline. This effect was only observed, however, when the prejunctional muscarinic autoinh ibitory effect of ACh was prevented with atropine. Both the RR- and SS -formoterol-induced increases in ACh release were abolished by the bet a(2)-antagonist ICI-118551 (3 x 10(-7) M). The effect of S-albuterol o n ACh release was variable, and the mean increase induced by 10(-5) M was 30.8 +/- 16.1% in the presence of atropine. In the muscle tension study, R- and RS-albuterol and RR- and RR/SS-formoterol (10(-8) to 10( -5) M) but not the S-enantiomers inhibited TSM contraction. Even thoug h R-enantiomers augment ACh release, they potently inhibit TSM contrac tion. Because racemic beta(2)-agonists are bronchodilators on acute ad ministration, the postjunctional spasmolytic effects of R-enantiomers predominate over the spasmogenic effect evoked via increased ACh relea se. The S-enantiomers, in contrast, do not inhibit TSM contraction and therefore would not contribute to the observed bronchodilation of the racemate. The S-enantiomers do prejunctionally facilitate ACh release when prejunctional muscarinic autoreceptors are dysfunctional, sugges ting a potentially deleterious effect.