CHARACTERIZATION OF THE TACHYKININ NEUROKININ-2 RECEPTOR IN THE HUMANURINARY-BLADDER BY MEANS OF SELECTIVE RECEPTOR ANTAGONISTS AND PEPTIDASE INHIBITORS

The tachykinin (NK2) receptor-mediating contraction of the human isola ted bladder to NKA was investigated by studying the affinities of eigh t structurally different receptor-selective antagonists (linear peptid es, cyclic peptides and pseudopeptides, non-peptide NK2 receptor antag onists). The affinities of the antagonists were compared to those meas ured for the same ligands at the NK2 receptors previously characterize d in the rabbit pulmonary artery and hamster trachea. In the presence of a cocktail of peptidase inhibitors (bestatin captopril and thiorpha n, 1 muM each) no significant correlation was found between pA2 values measured in the human bladder vs. those measured in the other two NK2 receptor-bearing preparation. In the presence of the aminopeptidase i nhibitor amastatin, however, pA2 values of linear antagonists bearing an N-terminal Asp residue MEN 10,207 and MEN 10,376 were significantly enhanced and these pA2 values were used for analysis; a significant c orrelation was found between pA2 values measured in the human urinary bladder and rabbit pulmonary artery. The pseudopeptide analog of NKA ( 4-10), MDL 28,564 which also bears a N-terminal Asp residue behaved as an agonist and its action was enhanced by amastatin. We conclude that the NK2 receptor-mediating contraction of the human urinary bladder s mooth muscle is similar to that previously characterized in the rabbit pulmonary artery (NK2A receptor category); in the human bladder smoot h muscle an amastatinsensitive peptidase (possibly aminopeptidase A) l imits biological activity of linear peptide derivatives of NKA bearing a N-terminal Asp residue.