Tachykinin antagonists inhibit nerve-mediated contractions in the circular muscle of the human ileum. Involvement of neurokinin-2 receptors.
The effects of some newly developed tachykinin antagonists that are selective for the neurokinin (NK)-1 (L 668,169) or the NK-2 (MEN 10,207, L 659,877 and R 396) tachykinin receptor on the cholinergic and noncholinergic contraction and on the nonadrenergic noncholinergic relaxation produced by electrical field stimulation (50 Hz) were investigated in mucosa-free circular strips of the human ileum. The strips were contracted by substance P and neurokinin A as well as by selective NK-2-receptor ligands, [beta Ala8]neurokinin A(4-10), and MDL 28,564, the latter peptide being capable of discriminating between NK-2-receptor subtypes. The selectivity of the antagonists for NK-1 or NK-2 receptors was confirmed in pharmacological experiments using substance P, neurokinin A, and [beta Ala8]neurokinin A(4-10) as stimulants. Among the NK-2-selective antagonists, MEN 10,207 displayed the highest affinity, followed by L 659,877 and R 396. The antagonists MEN 10,207 and L 659,877 inhibited the noncholinergic contraction to electrical stimulation in a concentration-dependent manner; L 668,169 and R 396 were poorly effective. Thus the potency of antagonists toward the noncholinergic response closely paralleled their rank order of potency at NK-2 receptors. The cholinergic contraction and nonadrenergic noncholinergic relaxation were not inhibited by the antagonists. Both substance P- and neurokinin A-like immunoreactivities were detected in extracts of the human ileum, and the identity of the corresponding peptides was confirmed by reverse-phase high-performance liquid chromatography. It was concluded that in addition to NK-1 receptors, the circular muscle of the human ileum also contains NK-2 receptors. Activation of the latter is chiefly responsible for the noncholinergic contraction to nerve stimulation.
Maggi
C A
CA
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Giuliani
S
S
Patacchini
R
R
Santicioli
P
P
Theodorsson
E
E
Barbanti
G
G
Turini
D
D
Giachetti
A
A
D000368:Aged; D000369:Aged, 80 and over; D001285:Atropine / Q000494:pharmacology; D004558:Electric Stimulation; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D066298:In Vitro Techniques; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D009424:Nervous System Physiological Phenomena; D015288:Neurokinin A / Q000378:metabolism; D011863:Radioimmunoassay; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D013373:Substance P / Q000032:analysis; D015320:Tachykinins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D015320:Tachykinins; D013373:Substance P; D013779:Tetrodotoxin; D001285:Atropine; D015288:Neurokinin A