Tachykinin NK(2) receptor mediates contraction and ion transport in rat colon by different mechanisms.
We have characterized the tachykinin NK(2) receptor-mediated contraction and vectorial ion transport responses in the muscularis mucosae and mucosa of the rat isolated distal colon, respectively. The tachykinin NK(2) receptor-selective antagonist nepadutant (c([(beta-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2beta-5beta))) produced competitive antagonism of [betaAla(8)]neurokinin A-(4-10)-induced contraction (pK(B) = 9.3) in the muscularis mucosae, and insurmountable blockade of increases in short-circuit current (I(sc)) responses (pK(B) = 8.6) in the mucosa. However, this latter effect was completely reversed by washout of the antagonist. [betaAla(8)]Neurokinin A-(4-10)-induced contractions were unaffected by indomethacin (3 microM). In sharp contrast, I(sc) responses induced by [betaAla(8)]neurokinin A-(4-10) (100 nM) were inhibited (>70%) by indomethacin (3 microM), while I(sc) responses to substance P (3 microM) were unchanged. Our study provides the first evidence that in the same organ stimulation of tachykinin NK(2) receptors leads to two independent responses mediated by different effector mechanisms both of which are blocked (albeit with different kinetics) by the potent and selective tachykinin NK(2) receptor antagonist, nepadutant.
Patacchini
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Pharmacology Department, Menarini Ricerche SpA Research Laboratories, Via Rismondo 12/A, 50131, Florence, Italy. chimfarm@menarini-richerche.it
Cox
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Ståhl
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Tough
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Maggi
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000502:physiology; D017136:Ion Transport / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000187:drug effects* / Q000502:physiology; D013373:Substance P / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; C107754:MEN 11420; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; C064218:neurokinin A (4-10), beta-Ala(8)-; D013373:Substance P; D015288:Neurokinin A; D007213:Indomethacin