Antisecretory and Relaxatory Effects of Tachykinin Antagonists in the Guinea-pig Intestinal Tract
| Autor: | Marie-France Porquet, Jon Goldhill, Norma Selve |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Quinuclidines medicine.medical_specialty Contraction (grammar) Muscle Relaxation Guinea Pigs Pharmaceutical Science Substance P Stimulation Biology Models Biological chemistry.chemical_compound Piperidines Tachykinins Internal medicine medicine Animals Secretion Intestinal Mucosa Pharmacology Antagonist Muscle Smooth Peptide Fragments Intestines Endocrinology Mechanism of action chemistry Benzamides medicine.symptom Tachykinin receptor Muscle contraction |
| Zdroj: | Journal of Pharmacy and Pharmacology. 51:1041-1048 |
| ISSN: | 2042-7158 0022-3573 |
| Popis: | Existing models used to study the mechanism of action and antagonism of tachykinergic effects on intestinal contraction and secretion suffer from technical problems and have not been fully characterized using specific tachykinin antagonists. Contraction of ileal segments by substance P, colonic circular muscle by β-alanine-neurokinin A, and longitudinal muscle by senktide were used as models for neurokinin-induced contraction in the guinea-pig. Guinea-pig colonic epithelial tissue was stimulated by substance P and senktide to assess NK1- and NK3-mediated secretion. Using these models the potency of therapeutically useful compounds was determined. NK1 and NK2 activation directly contracted smooth muscle, while NK1-mediated secretion was nerve-mediated. NK3 stimulation of contraction and secretion was neurally mediated, involving cholinergic nerves and 5-HT release. NK1-mediated contraction and secretion were antagonized by SR140333 (pD′2 = 9.29 and pKb = 8.53); NK2-mediated contraction was antagonised by SR48968 (pD′2 = 8.35) and NK3-mediated contraction and secretion were antagonized by SB223412 (pKb = 8.97 and 8.79). The mixed antagonist MDL103392 blocked NK1- and NK2-mediated contraction with pKb values of 7.92 and 6.71 respectively and NK1-mediated secretion with a pKb value of 6.57. This data characterizes existing tachykinin antagonists, and should orientate the development of improved compounds as therapies for intestinal disease. |
| Databáze: | OpenAIRE |
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