1.
SDZ PCO 400 evoked dose-related relaxation of isolated airway smooth muscle. For human bronchus precontracted by endogenous tone or addition of
carbachol (10(-5) M), IC50 values were 1.74 microM and 1.82 microM respectively. With guinea-pig trachea contracted by endogenous tone, a comparable IC50 (1.79 microM) was observed, but no IC50 (less than 100 microM) could be determined following contraction by
carbachol (10(-6) M). 2.
Airway obstruction induced by intravenous
bombesin in the anaesthetized ventilated guinea-pig was diminished by
intravenous injection of
SDZ PCO 400 (ID50 54 micrograms kg-1) or by introduction into the duodenum (ID50 1.0 mg kg-1). Inhalation of nebulized
SDZ PCO 400 (0.1 mg kg-1) diminished
airway obstruction due to
intravenous injection of
histamine (3.2-5.6 micrograms kg-1) for up to 20 min. 3. Increased bronchoconstrictor responses to
bombesin (180-240 ng kg-1) following
intravenous infusion of
platelet activating factor (PAF) or (+/-)-
isoprenaline, or to
histamine (1.0-3.2 micrograms kg-1) following
intravenous injections of
immune complexes, were suppressed following concomitant
intravenous infusion of
SDZ PCO 400 (ID50 0.3 mg kg-1 h-1, 1.0 mg kg-1 h-1 and 0.1 mg kg-1 h-1 respectively). 4.
Intravenous injection of
SDZ PCO 400 (0.1 mg kg-1) effected transient (less than 10 min) inhibition of
histamine-induced
bronchospasm, yet diminished, for prolonged periods [up to 40 min] the enhanced bronchoconstrictor responses to
histamine that followed
intravenous injections of
immune complexes.The capacity of
SDZ PCO 400 to resolve such established airway hyperreactivity was prevented by prior intraduodenal instillation of a
potassium channel antagonist,
glibenclamide (30 mg kg-').5. In sensitized guinea-pigs,
SDZ PCO 400 inhaled as a dry
powder (5.7 mg kg-') suppressed development of allergic airway hyperreactivity to
histamine (1.8-3.2;pg kg-', i.v.), but failed to diminish accumulation of eosinophils or other inflammatory cells within the airway lumen 24 h after inhalation of
ovalbumin.6. Preincubation (30 min) of isolated sensitized trachea of guinea-pig with
SDZ PCO 400 (10-5-10-4M) did not influence contractile responses to
ovalbumin. However in anaesthetized sensitized guinea-pigs,insufflation of
SDZ PCO 400 (1.25 mg) as a
powder substantially diminished
airway obstruction that followed inhalation of
ovalbumin. This effect was prevented by prior vagal section.7. It is concluded that
SDZ PCO 400 reduces
airway obstruction not only through direct actions on airway smooth muscle but also by impairing the expression of airway hyperreactivity, without directly influencing inflammatory events in the airways.