Tachykinin-induced dyspnea in conscious guinea pigs.
Aerosol administration of neurokinin A (NKA) or substance P (SP) to conscious guinea pigs produced labored abdominal breathing (dyspnea). Time to onset of dyspnea was inversely related to tachykinin concentration. Aerosol administration of the neutral endopeptidase inhibitor thiorphan significantly potentiated tachykinin-induced dyspnea without affecting responses to leukotriene D4 (LTD4), carbachol, histamine, platelet activating factor or serotonin (5-HT), indicating selectivity for tachykinins rather than a nonspecific effect on agonist reactivity. The rank order of potency for producing dyspnea was LTD4 greater than or equal to NKA (with thiorphan) much greater than SP (with thiorphan) greater than 5-HT = carbachol greater than histamine greater than platelet-activating factor. Pretreatment with propranolol, phentolamine, methysergide, pyrilamine or the peptide leukotriene antagonist, ICI 198,165, did not alter dyspnea induced by NKA or SP. The dose-response curves for NKA and SP were shifted to small degrees (less than 3-fold) to the right by atropine and to the left by indomethacin. Also, pretreatment with capsaicin did not affect responses to NKA or SP, indicating that they do not cause dyspnea by activating capsaicin sensitive C-fibers. These results suggest primarily direct effects of NKA and SP. This model may be useful for in vivo evaluation of tachykinin antagonists.
Kusner
E J
EJ
Department of Pharmacology, ICI Americas Inc., Wilmington, DE 19897.
Buckner
C K
CK
DeHaas
C J
CJ
Lengel
D J
DJ
Marks
R L
RL
Krell
R D
RD
D000336:Aerosols; D000818:Animals; D004347:Drug Interactions; D004417:Dyspnea / Q000139:chemically induced*; D006168:Guinea Pigs; D008297:Male; D015288:Neurokinin A / Q000008:administration & dosage / Q000633:toxicity*; D013189:SRS-A / Q000494:pharmacology; D013373:Substance P / Q000008:administration & dosage / Q000633:toxicity*; D015244:Thiorphan / Q000494:pharmacology
D000336:Aerosols; D013189:SRS-A; D013373:Substance P; D015288:Neurokinin A; D015244:Thiorphan