Inflammatory and motor responses by tachykinins in the guinea-pig oesophageal sphincter.
1. The aim of this study was to characterize the tachykinin receptors involved in producing plasma protein extravasation and contractile responses of the guinea-pig oesophageal sphincter. 2. In anaesthetized guinea-pigs, the selective tachykinin NK-1 receptor agonist [Sar9,Met(O2)11]substance P produced plasma protein extravasation (PPE) which was not affected by the treatment with the tachykinin NK-2 receptor antagonist MEN 10627 (1 micromol kg(-1) i.v.) or the histamine H1-receptor antagonist, diphenhydramine (34.5 micromol kg(-1) i.v.). However, the [Sar9,Met(O2)11]substance P-induced PPE was blocked by the previous administration of the peptide tachykinin NK-1 receptor antagonist FK 888 or by the non-peptide antagonist SR 140333, yielding ED50 values of 1.1 +/- 0.2 and 0.01 +/- 0.004 micromol kg(-1) i.v., respectively. 3. The tachykinin NK-2 or NK-3 receptor agonists [beta-Ala8]neurokinin A (4-10) or [MePhe7]neurokinin B, respectively, produced a weak PPE at high doses. The effect of [MePhe7]neurokinin B-induced PPE was inhibited by SR 140333. 4. In the guinea-pig isolated oesophageal sphincter, [Sar9,Met(O2)11]substance P did not exert any contractile effect up to 10 microM. The selective tachykinin NK-2 receptor agonist ([beta-Ala8]neurokinin A (4-10), produced concentration-dependent contractions (pD2 = 7.6 +/- 0.03) which were inhibited by the selective tachykinin NK-2 receptor antagonist, MEN 10627 (pA2 = 8.6 +/- 0.1). Also, the tachykinin NK-3 receptor selective agonist [MePhe7]neurokinin B induced concentration-dependent contractile responses, but these responses were inhibited by MEN 10627. 5. Altogether, these data indicate that the stimulation of tachykinin NK-1 receptor produces a vascular inflammatory response, while activation of tachykinin NK-2 receptors mediate the contraction of the guinea-pig oesophageal sphincter.
Conte
B
B
Pharmacology Department, Menarini Ricerche, Pomezia (Rome), Italy.
Parlani
M
M
Lopez
G
G
Cirillo
R
R
Maggi
C A
CA
Manzini
S
S
D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D004155:Diphenhydramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004943:Esophagogastric Junction / Q000187:drug effects; D005070:Evans Blue / Q000493:pharmacokinetics; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000037:antagonists & inhibitors*; D018039:Receptors, Tachykinin / Q000145:classification / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology*
D004151:Dipeptides; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; C062618:substance P, Sar(9)-Met(O2)(11)-; C078949:FK 888; C090951:MEN 10627; D013373:Substance P; D005070:Evans Blue; D004155:Diphenhydramine