Isbufylline, a xanthine derivative, inhibits bronchoconstrictor responses produced by stimulation of capsaicin-sensitive sensory nerves in guinea-pig: 'In vitro' and 'in vivo' evidence.

Isbufylline (1,3-dimethyl-7-isobutylxanthine) is a new xanthine derivative claimed to possess remarkable antibronchospastic properties coupled to reduced pro-convulsive side-effects. In guinea-pig bronchial preparations, isbufylline showed a differential and more pronounced, as compared to theophylline, relaxant activity on tonic bronchial contractions evoked by exogenous administration of equieffective concentrations of capsaicin (0.3 microM), neurokinin A (0.1 microM) and carbachol (0.3 microM) (in the presence of indomethacin 5 microM and thiorphan 10 microM). Isubfylline gave an IC50 of 21 (19-25, 95% confidence limits) microM on capsaicin-evoked contractile effects, and 36 (30-43) microM on carbachol-produced contractile effects, whilst it was almost ineffective in inhibiting neurokinin A-induced bronchospasm (IC50 not evaluable, > 100 microM). 'In vitro' studies were also performed using electrical field stimulation (EFS) to produce non-adrenergic non-cholinergic (NANC)- or cholinergic nerves-mediated contractions in guinea-pig isolated bronchi or trachea. Isbufylline (10-90 microM) produced a concentration-dependent inhibition of the NANC response (EFS: 20 Hz, supramaximal voltage, 0.5 ms pulse, width for 10 s) of bronchi (IC50 = 47 microM) without affecting the cholinergic contractile response in tracheal smooth muscle (EFS: 0.5 up to 32 Hz, supramaximal voltage, 0.5 ms pulse, for 15 s every min). The activity of isbufylline was also confirmed in anaesthetized guinea-pig showing a greater antibronchospastic activity towards capsaicin (8 nmol/kg i.v.) or vagal non-cholinergic (10 V, 1 ms, 20 Hz for 20 s) stimulation as compared to the inhibition exerted against acetylcholine (50 nmol/kg i.v.) or neurokinin A (1 nmol/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)