Premium
Tachykinin receptors in rabbit airways — characterization by functional, autoradiographic and binding studies
Author(s) -
Black J.L.,
Diment L.M.,
Alouan L.A.,
Johnson P.R.A.,
Armour C.L.,
BadgeryParker T.,
Burcher E.
Publication year - 1992
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.1476-5381.1992.tb12763.x
Subject(s) - neurokinin a , tachykinin receptor , substance p , receptor , medicine , endocrinology , contraction (grammar) , antagonist , neuropeptide , biology , muscle contraction , receptor antagonist , chemistry
1 In many species, both NK 1 and NK 2 tachykinin receptors appear to be important in mediating the contraction of airway smooth muscle. We have examined the distribution and characterization of receptors for tachykinins in rabbit airways using functional length tension studies, autoradiography and radioligand binding studies. 2 Contractile responses to tachykinins were elicited in four different areas of the respiratory tree — trachea, and three progressively more distal areas of the right bronchus. The NK 2 receptor‐preferring agonists, neurokinin A (NKA), neuropeptide gamma (NPγ) and the NK 2 ‐selective [Lys 5 MeLeu 9 , Nle 10 ]‐NKA(4–10) [NKA (4–10) analogue] produced similar contraction in all four areas. Substance P (SP) and the NK 1 ‐selective [Sar 9 ,Met(O 2 ) 11 ]‐SP (Sar‐SP) exhibited a marked location‐dependence in the magnitude of contraction, producing minimal contraction in the trachea and more proximal bronchi with contractions becoming progressively larger in the more distal airways. Senktide (which is selective for the NK 3 receptor) produced negligible contraction in all areas. 3 The NK 2 ‐selective antagonist, MDL29,913, was a weak antagonist of NKA and NKA(4–10) analogue. At a concentration of 2 μ m , it produced a small but significant shift in the response curve to NKA and a greater shift (8 fold) in the curve to NKA(4–10) analogue, but it had no effect on responses to Sar‐SP. The non peptide NK, receptor antagonist, CP‐96,345, was also unexpectedly weak in this preparation. The pD 2 value for Sar‐SP was decreased 27 fold by CP‐96,345 at a concentration of 1 μ m , without alteration in the maximum response. 4 Autoradiographic binding sites to [ 125 I]‐NKA were sparse over smooth muscle in proximal airway preparations and markedly increased in density in the more distal airways. There was negligible binding over vascular smooth muscle and epithelium. 5 Radioligand binding studies revealed binding to [ 125 I]‐NKA which was 82% specific. The order of potency for inhibition of [ 125 I]‐NKA binding was SP >= Sar‐SP > NKA = NPγ>CP‐96,345 > NKA (4–10) analogue > NKB ⋙ MEN 10207 (the NK 2 subtype selective antagonist) > MDL 29,913 > senktide. This profile indicates binding predominantly to NK 1 receptors. 6 These results suggest that there are at least two types of tachykinin receptors in rabbit airways, a population of NK 1 receptors, the density of which is greatest in the periphery and, in addition, NK 2 receptors which are uniformly distributed throughout the airways. These receptors have unusual characteristics in that the NK 1 antagonist, CP‐96,345 and the NK 2 antagonist, MDL 29,913 respectively exhibited only weak potency.