Effect of YM934, a KATP channel opener, on airway hyperresponsiveness induced by platelet activating factor in guinea-pigs.
The effect of YM934 (2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1, 4-benzoxazin-4-yl)pyridine N-oxide) on airway hyperresponsiveness induced by platelet activating factor (PAF) was investigated in anesthetized guinea-pigs. Bronchoconstrictor responses to histamine were enhanced by intravenous (i.v.) infusion of PAF (600 ng/kg/h for 1 h). The KATP channel opener, YM934 (10-100 micrograms/ kg), given by i.v. bolus injection or i.v. infusion (75 min) dose-dependently inhibited this PAF-induced airway hyperresponsiveness. In the normal control group, i.v. bolus injection of YM934 dose-dependently reduced the bronchoconstrictor responses to histamine. However, i.v. infusion of YM934 (100 micrograms/kg) had almost no effect on responsiveness. Pretreatment with capsaicin (50 micrograms/kg, s.c.), a depleter of neuropeptides, partially prevented the development of PAF-induced airway hyperresponsiveness. In contrast, phosphoramidon (2.5 mg/kg, i.v.), an inhibitor of neutral endopeptidase, enhanced the airway hyperresponsiveness induced by PAF. Furthermore, YM934 inhibited PAF-induced airway hyperresponsiveness in guinea-pigs pretreated with capsaicin or phosphoramidon. The present results suggest that YM934 given by i.v. infusion reduces PAF-induced airway hyperresponsiveness at doses insufficient to produce a bronchodilatory effect. Further, the mechanism of YM934's inhibitory effect on airway hyperresponsiveness may involve bronchodilatory and other unidentified effects, such as a decrease in the release of neuropeptides from sensory nerve terminals.
Saitoh
C
C
Clinical Pharmacology Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan.
Ishikawa
J
J
Asano
M
M
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D048588:Benzoxazines; D002211:Capsaicin / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D010078:Oxazines / Q000008:administration & dosage / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000633:toxicity; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000517:prevention & control*
D018927:Anti-Asthmatic Agents; D048588:Benzoxazines; D003497:Cyclic N-Oxides; D006020:Glycopeptides; D010078:Oxazines; D010972:Platelet Activating Factor; D015221:Potassium Channels; D002211:Capsaicin; C008890:phosphoramidon; C084963:2H-1,4-benzoxazine, 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridinyl)-, N-oxide