Sensory nerves in the airways as a target for drug development.
1. Electrical stimulation (2.5-10 Hz, 80 V, 1 ms for 15 s) within the spinal canal of the pithed guinea-pig pretreated with atropine, D-tubocurarine and pentolinium caused a bronchoconstrictor response, indicated by a rise of insufflation pressure. 2. The magnitude of these non-cholinergic neuronal bronchoconstrictor responses were frequency-dependent, capsaicin-sensitive and temperature-dependent. 3. Responses could be inhibited by the alpha 2-adrenoceptor agonist B-HT920 (3 mg/kg, i.v.) and the mu-opioid agonist H-Tyr-D-Arg-Phe-Lys-NH2 (DALDA; 1 mg/kg, i.v.) and the attenuation observed could be overcome by use of the respective antagonists idazoxan (3 mg/kg, i.v.) and naloxone (3 mg/kg, i.v.). 4. Substance P-induced bronchoconstriction (0.3 micrograms/kg, i.v.), but not that due to electrical stimulation, was attenuated by indomethacin (3 mg/kg, i.v.), indicating an indirect action of substance P via a product of arachidonic acid metabolism. 5. The prostanoid product of the substance P response was probably thromboxane A2. 6. Hence, novel drug development could be directed towards tachykinin receptors or to the synthesis, release and degradation of neuropeptides.
Rechtman
M P
MP
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology*; D001980:Bronchi / Q000294:innervation*; D016084:Bronchoconstriction / Q000187:drug effects*; D002211:Capsaicin / Q000494:pharmacology; D015195:Drug Design; D004558:Electric Stimulation; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects; D017450:Receptors, Opioid, mu; D013373:Substance P / Q000494:pharmacology; D013696:Temperature
D000316:Adrenergic alpha-Agonists; D001381:Azepines; D009842:Oligopeptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C063076:tyrosyl-arginyl-phenylalanyl-lysinamide; D016718:Arachidonic Acid; D013373:Substance P; C024763:talipexole; D002211:Capsaicin; D007213:Indomethacin