Neural 5-HT4 receptors in the human isolated detrusor muscle: effects of indole, benzimidazolone and substituted benzamide agonists and antagonists.

摘要: 1. In strips of human isolated detrusor muscle, the 5-hydroxytryptamine (5-HT) receptor (5-HT4) that mediates facilitation neuromuscular cholinergic transmission was further characterized by using 5-HT and a series ligands known for their 5-HT4 agonist (5-methoxytryptamine: 5-MeOT, cisapride, (R,S)-zacopride, BIMU 8) or antagonist (RS 23597, GR 125487, DAU 6285) properties. 2. presence methysergide (1 microM) ondansetron (3 to isolate pharmacologically receptors, (0.3 nM-1 microM), 5-MeOT (10 nM -30 8 nM-3 cisapride (0.1-10 (R,S)-zacopride (0.1-30 potentiated contractions electrical field stimulation in concentration-dependent manner. RS 23597 nM-10 competitive other systems, also showed The following rank order potency as an obtained: (pEC50 = 8.0) > (7.0) (6.9) (6.6) (6.0) (5.7). Relative (intrinsic activity 1), acted full (1.03), while (0.76), (0.61), (0.60) (0.41) behaved partial agonists. 3. potentiation competitively antagonized selective 125487 (0.3-3 nM) with pA2 estimate 9.75 (Schild slope 1.09), 6285 microM; pK3 6.45). Additionally, responses (pKB 9.72) reversed induced 23597. As antagonist, (10, 30 100 inhibited response 5-HT. addition, reduced maximum 50%, respectively. pKB value calculated at 10 8.0. 4. Thus, receptors mediating are activated indoleamines (5-HT, 5-MeOT), substituted benzamide (cisapride, (R,S)-zacopride), benzoate 23597) benzimidazolone (BIMU derivatives. activities (in terms both efficacy) most agonists, well affinity estimates antagonists 6285, comparable those found peripheral tissues. Exceptions which either 5-HT1 unusually low potency. latter findings may be ascribed differences efficiency coupling mechanisms and/or molecular structure (i.e. splice variants) receptor.