Substance P antagonists and the role of tachykinins in non-cholinergic bronchoconstriction.
Electrical field stimulation of guinea-pig isolated hilus bronchi induced tetrodotoxin-sensitive contractions of which only a minor part could be inhibited by atropine. The remaining non-cholinergic bronchoconstriction was antagonized by a heptapeptide and an undecapeptide substance P (SP) analogue (Arg5, D-Trp7,9) SP5-11, IC50 = 24.0 microM and (D-Pro2, D-Trp 7,9) SP, IC50 = 10.0 microM. Of the exogenously added tachykinins, both eledoisin (8 times) and physalaemin (3 times) were more potent bronchoconstrictors than SP. Pretreatment with the SP-analogues shifted concentration-response curves to the tachykinins to the right, eledoisin being most readily antagonized. (Arg5, D-Trp 7,9) SP 5-11 also antagonized the neural response more readily than that of SP. In addition, in the frog isolated sciatic nerve preparation the two SP-analogues were found to possess potent lidocaine-like neurodepressant actions which further complicated the interpretation of the neural inhibitory effects of these compounds. It is concluded that if a tachykinin contributes to non-cholinergic bronchoconstriction, an eledoisin-like peptide is a more likely candidate than SP itself. Since SP-antagonists may have local anaesthetic properties their value as tools in neurophysiology seems limited. Inferentially, the non-cholinergic bronchoconstrictive neurotransmitter remains to be identified.
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D003251:Constriction, Pathologic / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004600:Eledoisin / Q000494:pharmacology*; D006168:Guinea Pigs; D007705:Kinins / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D010803:Physalaemin / Q000494:pharmacology*; D011894:Rana pipiens; D012584:Sciatic Nerve / Q000187:drug effects; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D007705:Kinins; D010446:Peptide Fragments; D010803:Physalaemin; D013373:Substance P; D013779:Tetrodotoxin; D004600:Eledoisin; D001285:Atropine; C032132:substance P, prolyl(2)-tryptophan(7,9)-; C043953:substance P (5-11), Arg(5)-Trp(7,9)-