CHARACTERIZATION OF THE TACHYKININ NK2 RECEPTOR IN THE HUMAN BRONCHUS- INFLUENCE OF AMASTATIN-SENSITIVE METABOLIC PATHWAYS

1 The aim of this study was to characterize the tachykinin NK2 recepto r subtype mediating the spasmogenic response in the human isolated bro nchus. The motor response to neurokinin A (NKA) and the selective NK2 agonist [beta Ala(8)]NKA(4-10), as well as the antagonistic effects of cyclic (L659,877) and linear (MEN 10376) peptide NK2 antagonists were assessed in the presence or absence of amastatin (an inhibitor of ami nopeptidases A and M). 2 NKA was more potent than [beta Ala(8)]NKA(4-1 0) in eliciting bronchoconstriction (pD(2) being 7,43 and 6,87 respect ively). In the presence of amastatin (1 mu M), the estimated affinity of [beta Ala(8)]NKA(4-10), but not that of NKA, was significantly incr eased to yield a pD(2) of 7,44. 3 L659,877 and MEN 10376 inhibited [be ta Ala(8)]NKA(4-10)-induced contraction with similar affinities; pA(2) values were 5.7 +/- 0.22 and 6.3 +/- 0.32, respectively. Amastatin (1 mu M) increased the potency of MEN 10376 to 7.28 +/- 0.46, whereas th at of L659,877 was unaffected. 4 In the presence of amastatin the pseu dopeptide MDL 28,564 behaved as a partial agonist. 5 We conclude that the NK2 receptor subtype present in the human bronchus has properties similar to those described for the circular muscle of the human colon and thus may be classified as a 'NK2A' subtype. We show that the appar ent potency of peptides, bearing N-terminal acidic residues, is influe nced by an amastatin-sensitive peptidase, possibly aminopeptidase A.