Effects of a potassium channel opener (SDZ PCO 400) on guinea-pig and human pulmonary airways.
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.
Chapman
I D
ID
Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
Kristersson
A
A
Mathelin
G
G
Schaeublin
E
E
Mazzoni
L
L
Boubekeur
K
K
Murphy
N
N
Morley
J
J
D000402:Airway Obstruction / Q000139:chemically induced / Q000188:drug therapy; D000818:Animals; D001578:Benzopyrans / Q000627:therapeutic use*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000494:pharmacology; D003517:Cyclopentanes / Q000627:therapeutic use*; D004802:Eosinophilia / Q000139:chemically induced; D006168:Guinea Pigs; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010047:Ovalbumin / Q000276:immunology; D010276:Parasympatholytics / Q000627:therapeutic use*; D015221:Potassium Channels / Q000187:drug effects*; D005719:gamma-Globulins / Q000276:immunology
D001578:Benzopyrans; D001993:Bronchodilator Agents; D003517:Cyclopentanes; D010276:Parasympatholytics; D015221:Potassium Channels; D005719:gamma-Globulins; C073091:SDZ PCO 400; D010047:Ovalbumin