Effects of a potassium channel opener (SDZ PCO 400) on guinea‐pig and human pulmonary airways

Abstract

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 μm and 1.82 μm respectively. With guinea‐pig trachea contracted by endogenous tone, a comparable IC50 (1.79 μm) was observed, but no IC50 (< 100 μm) could be determined following contraction by carbachol (10−6 m). Airway obstruction induced by intravenous bombesin in the anaesthetized ventilated guinea‐pig was diminished by intravenous injection of SDZ PCO 400 (ID50 54 μg 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 μg kg−1) for up to 20 min. 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 μg 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). Intravenous injection of SDZ PCO 400 (0.1 mg kg−1) effected transient (< 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−1). In sensitized guinea‐pigs, SDZ PCO 400 inhaled as a dry powder (5.7 mg kg−1) suppressed development of allergic airway hyperreactivity to histamine (1.8–3.2 μg kg−1, i.v.), but failed to diminish accumulation of eosinophils or other inflammatory cells within the airway lumen 24 h after inhalation of ovalbumin. Preincubation (30 min) of isolated sensitized trachea of guinea‐pig with SDZ PCO 400 (10−5−10−4 m) 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. 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.

Effect of YM934, a KATP channel opener, on airway hyperresponsiveness induced by platelet activating factor in guinea-pigs

“…The suitability of this PAF-induced airway hyperresponsiveness model as a basis for anti-asthma drug selection has been recognized (Mazzoni et al 1985;Sanjar et al 1989;Chapman et al 1992;Perretti et al 1995). Airway response is represented as a bronchoconstriction-associated increase in airway resistance or pulmonary insufflation pressure.…”

KCO912: a potent and selective opener of ATP-dependent potassium (K ATP ) channels which suppresses airways hyperreactivity at doses devoid of cardiovascular effects

“…Experiments were conducted essentially as described by Chapman et al (1992). Guinea pigs were anaesthetised with phenobarbitone (100 mg/kg i.p.)…”

In vitro and in vivo effects of SCA40 on guinea pig airways

“…to induce airways hyperreactivity) in guinea pigs (Chapman et al 1992). Although the precise mechanism of action is unknown, immune complex-induced airways hyperreactivity can be reversed by openers of ATP-dependent potassium channels and by b-adrenoceptor agonists such as salbutamol Chapman et al 1992).…”