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)
Meini
S
S
Istituto Farmacobiologico Malesci, Research Laboratories, Florence, Italy.
Ballati
L
L
Evangelista
S
S
Manzini
S
S
D015056:1-Methyl-3-isobutylxanthine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000294:innervation*; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002211:Capsaicin / Q000037:antagonists & inhibitors*; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002794:Choline / Q000502:physiology; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D013268:Stimulation, Chemical; D013806:Theophylline / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000294:innervation; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D015288:Neurokinin A; D002217:Carbachol; C058878:isbufylline; D013806:Theophylline; D002794:Choline; D000109:Acetylcholine; D002211:Capsaicin; D015056:1-Methyl-3-isobutylxanthine