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Competitive antagonists discriminate between NK 2 tachykinin receptor subtypes
Author(s) -
Maggi Carlo Alberto,
Patacchini Riccardo,
Giuliani Sandro,
Rovero Paolo,
Dion Stephane,
Regoli Domenico,
Giachetti Antonio,
Meli Alberto
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb15851.x
Subject(s) - neurokinin a , tachykinin receptor , substance p , thiorphan , peptide , receptor , chemistry , neurokinin b , medicine , eledoisin , endocrinology , antagonism , pharmacology , biology , neuropeptide , biochemistry , neprilysin , enzyme
1 We have compared the ability of various tachykinins and selective tachykinin receptor agonists to induce contraction of the endothelium‐denuded rabbit pulmonary artery (RPA) and hamster trachea (HT) and have estimated the affinity of some newly developed NK 2 selective antagonists in the same tissues. 2 In confirmation of previous findings, experiments with the agonists indicated that NK 2 receptors are the main if not the sole mediators of the response to tachykinins in both RPA and HT. No evidence for significant degradation of neurokinin A (NKA) was found in either tissue when experiments were repeated in the presence of a mixture of peptidase inhibitors (thiorphan, captopril and bestatin, 1 μ m each). 3 The peptide antagonists tested were: Peptide I = [Tyr 5 , d ‐Trp 6,8,9 , Arg 10 ]‐NKA(4–10); Peptide II = [Tyr 5 , d ‐Trp 6,8,9 , Arg 10 ]‐NKA(3–10); Peptide III = Ac‐Leu‐Asp‐Gln‐Trp‐Phe‐Gly‐NH 2 . The three peptides produced a concentration‐dependent rightward shift of the concentration‐response curve to NKA in both RPA and HT with no significant depression of the maximal response attainable. The slopes of the Schild plots were not significantly different from unity, indicating a competitive antagonism. Peptides I and II were about 100 times more potent in the RPA than in the HT, while Peptide III was about 100 times more potent in the HT than RPA. 4 The pA 2 values obtained in these two tissues with the three antagonists were not significantly different when tested in the absence or presence of peptidase inhibitors, or when a selective NK 2 receptor agonist, [βAla 8 ]‐NKA(4–10) was used instead of NKA. Similar pA 2 values were obtained after 15 or 90 min of incubation with the antagonists. Peptides I, II and III had no inhibitory effect on contractions produced by noradrenaline in the RPA or by carbachol in the HT. 5 Peptides I, II and III showed weak or no antagonistic activity toward the vasodilatator effect of substance P in the dog carotid artery (NK 1 receptor‐mediated) or toward the contractile effect of neurokinin B in the rat portal vein (NK 3 receptor‐mediated). 6 These results provide pharmacological evidence for heterogeneity of NK 2 receptors in the RPA and HT. The NK 2 receptors present in these tissues are not discriminated by natural tachykinins or selective agonists, but are recognized with very different affinity by NK 2 receptor antagonists.