1. Experiments have been performed with the dual intent of analysing the mechanism by which
AH 21-132 relaxes airways smooth muscle and determining whether the effects of this compound can be distinguished from those of
theophylline. 2.
AH 21-132 (0.25-8 microM) and
theophylline (1-1000 microM) each caused concentration-dependent suppression of the spontaneous tone of guinea-pig isolated trachealis. The maximal effect of
AH 21-132 was equivalent to that of
theophylline. No evidence was obtained that the tissue became sensitized or desensitized to the action of
AH 21-132. 3.
Propranolol (1 microM) profoundly antagonized the tracheal relaxant action of
isoprenaline but not that of
AH 21-132. 4. In
indomethacin (2.8 microM)-treated tissues, tone was induced by K+-rich (120 mM)
Krebs solution,
acetylcholine (ACh, 1 mM) or
histamine (200 microM). Log concentration-relaxation curves for
AH 21-132,
isoprenaline and
theophylline were all moved to the right in the presence of the spasmogens, the smallest rightward shift being induced by
histamine and the greatest by ACh. While maximal effects of
AH 21-132 and
theophylline were unaffected by the spasmogens, that of
isoprenaline was reduced by KCl and ACh. 5. In tissues treated with
indomethacin (2.8 microM),
AH 21-132 (0.1-100 microM) inhibited the spasmogenic effects of
potassium chloride (KCl), ACh and
histamine in a concentration-dependent manner. The inhibition was characterized by rightward shifts in the spasmogen concentration-effect curves with depression of their maxima. 6. In tissues treated with both
indomethacin (2.8 microM) and ACh (1 mM), the removal of tracheal epithelium caused a small but significant leftward shift in the log concentration-relaxation curve for
AH 21-132 but did not alter that for
theophylline. 7. In tissues treated with
indomethacin (2.8 microM) and maintained at 12 degrees C,
theophylline (0.1-3.2 mM) caused concentration-dependent
spasm. This effect was not shared by
AH 21-132. 8.
AH 21-132 (0.1-1000 microM) more potently inhibited the activity of
cyclic AMP-dependent than of
cyclic GMP-dependent
phosphodiesterase derived from homogenates of guinea-pig trachealis.
Theophylline, too, inhibited these
enzymes but was less potent in each case than
AH 21-132 and did not exhibit selectivity for the
cyclic AMP-dependent
enzyme. 9. It is concluded that
AH 21-132 exerts a non-specific (i.e. effective no matter what agent is used to support tone) relaxant effect on the trachealis muscle which does not involve the activation of beta l-
adrenoceptors. The profile of the relaxant action of
AH 21-132 more closely resembles that of
theophylline than that of
isoprenaline. However,
AH 21-132 can be differentiated from
theophylline in that: (a) its relaxant potency is increased by epithelial removal; (b) it does not cause tracheal
spasm; (c) it exhibits selectivity as an inhibitor of
cyclic AMP-dependent as opposed to
cyclic GMP-dependent
phosphodiesterase. It is possible that the relaxant effects of
AH 21-132 are related to its ability to inhibit
cyclic nucleotide phosphodiesterases.