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 (EC(50) = 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 (pA(2) = 6.7), R396 (pA(2) = 6.1), (+/-)SR48968 (pA(2) = 8.4) and GR159897 (pA(2) = 8.6), but not by the NK1-receptor blocking drug, GR82334 (pA(2) < 5). In approximately half of the preparations, the peptidase inhibitors, phosphoramidon (1 mu M) and bestatin (100 mu M), caused a marked and well-maintained contraction (similar to 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.