Further evidence that tachykinin-induced contraction of human isolated bronchus is mediated only by NK2-receptors.
The tachykinin-receptors mediating contraction of human bronchus have been characterized using both tachykinin-receptor selective agonists and blocking drugs under conditions where tachykinin metabolism by endogenous peptidases has been controlled, and true equilibrium conditions have been established. The findings that neurokinin A (EC50 = 2 nM) is the most potent agonist, and the NK2-receptor selective agonist, GR64349, is only 3-fold weaker, whereas agonists selective for NK1-receptors, substance P methyl ester, or NK3-receptors, senktide, are inactive, suggest that this effect is mediated exclusively by NK2-receptors. This is supported by observations that GR64349 is antagonised by the selective NK2-receptor blocking drugs, MEN10207 (pA2 = 6.7), R396 (pA2 = 6.1), (+/-)SR48968 (pA2 = 8.4) and GR159897 (pA2 = 8.6), but not by the NK1-receptor blocking drug, GR82334 (pA2 < 5). In approximately half of the preparations, the peptidase inhibitors, phosphoramidon (1 microM) and bestatin (100 microM), caused a marked and well-maintained contraction (approximately 20% of neurokinin A maximum), which may indicate a role for endogenous tachykinins in the regulation of tone in this preparation. This is supported by the finding that neurokinin A-immunoreactive nerve fibres are located around intrinsic neurones of local ganglia and within the smooth muscle layer of this preparation.
Sheldrick
R L
RL
Department of Pharmacology, Glaxo Research and Development Ltd, Ware, Hertfordshire, UK.
Rabe
K F
KF
Fischer
A
A
Magnussen
H
H
Coleman
R A
RA
D000368:Aged; D001980:Bronchi / Q000187:drug effects / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D015287:Neurokinin B / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology; D015320:Tachykinins / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D006020:Glycopeptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; C068031:neurokinin A (3-10), lysyl(3)-glycyl(8)-R-lactam-leucine(9)-; D013373:Substance P; D015288:Neurokinin A; D015287:Neurokinin B; D002217:Carbachol; C008890:phosphoramidon