The benzonaphthyridine derivative,
AH 21-132, has non-specific relaxant effects in isolated airways smooth muscle. The action of
AH 21-132 in trachealis muscle is not antagonised by
propranolol but
AH 21-132 is slightly potentiated by epithelium removal. Electrophysiological recording from guinea-pig trachealis shows that AH 21-132-induced relaxation is accompanied by suppression of electrical slow waves and by cellular hyperpolarisation. Unlike
theophylline,
AH 21-132 does not cause
spasm of cooled (12 degrees C),
indomethacin-treated trachealis muscle, nor does it act as an antagonist at
adenosine A1 receptors.
AH 21-132 does not depress the Ca2+ sensitivity or responsiveness of
Triton X-100 skinned trachealis fibres. In tracheal relaxant concentrations,
AH 21-132 selectively inhibits
cAMP phosphodiesterase (PDE) compared with cGMP-PDE. The (-)-enantiomer of
AH 21-132 is more potent than its (+)-enantiomer both in causing tracheal relaxation and in inhibiting cAMP-PDE. When tested on PDE
isoenzymes separated from bovine trachealis and guinea-pig cardiac ventricles,
AH 21-132 exhibits selectivity as an inhibitor of the
isoenzyme types III and IV.
AH 21-132 increases the trachealis content of cAMP and cGMP, but only in concentration greater than that required fully to suppress the mechanical tone of the tissue.
AH 21-132 has
bronchodilator activity in anaesthetised, ventilated guinea-pigs when administered intraduodenally, intravenously or by inhalation. Inhaled
AH 21-132 also provides bronchodilatation in healthy human volunteers in whom bronchoconstriction has been induced by inhaled
methacholine.