Contractile effect of tachykinins on Suncus murinus (house musk shrew) isolated ileum.
Recent studies used Suncus murinus to investigate the anti-emetic potential of NK(1) tachykinin receptor antagonists. However, the pharmacology of tachykinin receptors in this species has not been fully characterized. In the present studies, therefore, we examined a range of tachykinin receptor agonists for a capacity to induce contractions of the isolated ileum. The tachykinin NK1 receptor preferring agonists substance P, septide and [Sar9Met(O2)11] substance P, and the tachykinin NK2 preferring agonists neurokinin A and GR 64349 (Lys-Asp-Ser-Phe-Val-Gly-R-gamma-lactam-Leu-Met-NH2) caused concentration dependent contractions with EC50 values in the nanomolar range. However, the tachykinin NK3 preferring agonists neurokinin B and senktide (1nM-1microM) induced only weak contractions. The action of senktide, but not [Sar9Met(O2)11] substance P, septide, or GR 64349, was antagonized significantly by atropine (P<0.05); tetrodotoxin and hexamethonium were inactive. The tachykinin NK1 receptor antagonist CP-99,994 ((+)-[(2S,3S)-3-(2-methoxy-benzyl-amino)-2-phenylpiperidine]) (10-100nM) inhibited substance P- and septide-induced contractions non-competitively. The pA2 value estimated for CP-99,994 against septide was 7.3+/-0.1. It also non-competitively antagonized the contractile responses induced by [Sar9Met(O2)11] substance P with a pA2 of 7.4+/-0.1. CP-99,994 also had a slight inhibitory action on neurokinin A-induced contractions, but did not modify the action of GR 64349. Conversely, the tachykinin NK2 receptor antagonist, saredutant, competitively antagonized GR 64349-induced contractions with a pA2 of 7.34+/-0.02. On the other hand, the presence of both CP-99,994 and saredutant competitively antagonized substance P-induced contraction. The present studies indicate that tachykininNK1 and NK2 receptors exist in the ileum of S. murinus and are involved in mediating contractions directly on smooth muscle, whereas tachykinin NK3 receptors may play a minor role involving a release of acetylcholine.
Cheng
Frankie H M
FH
Emesis Research Group, Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
Chan
Sze Wa
SW
Rudd
John A
JA
D000818:Animals; D001285:Atropine / Q000378:metabolism / Q000494:pharmacology; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology; D018738:Hexamethonium / Q000378:metabolism / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects*; D008297:Male; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015287:Neurokinin B / Q000378:metabolism / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D018733:Nicotinic Antagonists / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000819:agonists* / Q000378:metabolism*; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000378:metabolism; D012788:Shrews / Q000033:anatomy & histology / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015320:Tachykinins / Q000378:metabolism / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000378:metabolism / Q000494:pharmacology
D001549:Benzamides; D018727:Muscarinic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D026941:Sodium Channel Blockers; D015320:Tachykinins; C054724:senktide; C068031:neurokinin A (3-10), lysyl(3)-glycyl(8)-R-lactam-leucine(9)-; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D018738:Hexamethonium; D013779:Tetrodotoxin; C073839:SR 48968; C054725:septide; D001285:Atropine; D015288:Neurokinin A; D015287:Neurokinin B; D011761:Pyrrolidonecarboxylic Acid