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Query: UNIPROT:P20366 (substance P)
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Agonist-induced desensitization has been utilized to discriminate and independently "isolate" the neuronal excitatory receptors to 5-hydroxytryptamine (5-HT) in the guinea pig ileum (5-HT3 and putative 5-HT4 receptors). Electrically stimulated longitudinal muscle myenteric plexus preparations, and non-stimulated segments of whole ileum were used. Exposure to 5-methoxytryptamine (10 mumol/l) inhibited completely responses to 5-HT at the putative 5-HT4 receptor without affecting 5-HT3-mediated responses. Conversely, exposure to 2-methyl-5-HT (10 mumol/l) inhibited completely responses to 5-HT at the 5-HT3 receptor without affecting putative 5-HT4-mediated responses. The inhibition with 5-methoxytryptamine and 2-methyl-5-HT, either alone or in combination, appeared selective as responses to KCl, DMPP, carbachol, histamine, and substance P were unaffected or only very slightly modified. Furthermore, the pA2 values for ICS 205-930 at the putative 5-HT4 (pA2 = 6.2 to 6.5) and 5-HT3 (pA2 = 7.6 to 8.1) receptors (estimated in the presence of 2-methyl-5-HT and 5-methoxytryptamine, respectively) were consistent with those estimated in the absence of desensitization. 5-Methoxytryptamine, but not 2-methyl-5-HT, suppressed completely but reversibly the concentration-effect curve to renzapride, suggesting that responses to this agent are mediated exclusively via agonism at the putative 5-HT4 receptor. It is concluded that 5-methoxytryptamine and 2-methyl-5-HT can be utilized as selective probes to discriminate the putative 5-HT4 receptor from the 5-HT3 receptor in guinea pig ileum. This finding is of importance as no selective antagonist exists for the putative 5-HT4 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine-induced desensitization as a discriminative tool for the 5-HT3 and putative 5-HT4 receptors in guinea pig ileum. 240 3

1. The involvement of neurokinins in the non-cholinergically-mediated contractile response induced by stimulation of 5-HT3 and 5-HT4 receptors has been examined in the longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum. 2. The 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT), showed a lower potency in this preparation than the more selective 5-HT4 receptor agonist 5-methoxytryptamine. The effect of both drugs was markedly reduced by atropine. 3. Substance P (SP) and neurokinin B (NKB) produced biphasic concentration-response curves in the preparation. Neurokinin A (NKA), the NK1 receptor agonist, [Sar9,Met(O2)11]SP and the NK3 receptor agonist, senktide yielded monophasic concentration-response curves. 4. After desensitization of the NK1 receptor with SP or [Sar9,met(O2)11]SP, in the presence of atropine, the contractile response to 2-methyl-5-HT was entirely blocked. Desensitization of NK3 receptors with NKB, also in the presence of atropine, fully suppressed the 5-HT4 receptor-mediated contraction evoked by 5-methoxytryptamine. 5. In preparations prelabelled with [3H]-choline, SP produced a concentration-dependent increase in tritium overflow, an index of [3H]-acetylcholine release, while an inverse relationship was found with NKB. At low neurokinin concentrations, the releasing effect of NKB was much more marked. 6. It is suggested that in the response to 5-HT3 receptor stimulation, there is a role for SP and acetylcholine. NKB appears to be preferentially involved in the release of acetylcholine elicited by stimulation of 5-HT4 receptors.
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PMID:Involvement of neurokinins in the non-cholinergic response to activation of 5-HT3 and 5-HT4 receptors in guinea-pig ileum. 751 54

5-Hydroxytryptamine (5-HT) has been demonstrated to cause both constriction and relaxation of guinea pig airways, partly through direct action on airway smooth muscle and partly through postganglionic facilitation of cholinergic neurotransmission. We performed an in vitro study to investigate whether 5-HT can modulate the noncholinergic contraction in guinea pig airways due to release of neuropeptides from airway sensory nerves. In the presence of atropine (1 microM), ketanserin (10 microM), and indomethacin (10 microM), 5-HT (0.1-100 microM) produced concentration-dependent inhibition of electrical field stimulation-induced noncholinergic contraction with maximal inhibition of approximately 72 +/- 4%. Tropisetron (ICS-205-930, 1 microM), a 5-HT3 and 5-HT4 receptor antagonist, was unable to prevent the inhibition produced by 5-HT. Methiothepin (1-100 nM), a 5-HT1 and 5-HT2 receptor antagonist, produced a concentration-dependent inhibition of the effect of 5-HT (1 microM) with a 50% inhibition concentration value of 66 nM. 5-HT (100 microM) had no effect on the cumulative concentration-response relationship to exogenous substance P (10 nM-10 microM). The concentration of agonist causing 35% inhibition of the noncholinergic contraction (EC35) was calculated, and a rank order of potency was established: 5-carboxamidotryptamine (EC35 = 0.24 microM) > 5-HT (EC35 = 0.77 microM) > 8-hydroxy-2-(dipropylamino)tetralin (EC35 = 8.1 microM) > sumatriptan (EC35 = 18 microM). We conclude that 5-HT concentration dependently modulates noncholinergic contraction in guinea pig airways in vitro by a prejunctional mechanism. This effect is probably mediated through a 5-HT1-like receptor; however, the exact subtype remains to be elucidated.
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PMID:5-HT modulates noncholinergic contraction in guinea pig airways in vitro by prejunctional 5-HT1-like receptor. 753 Jul 4

1. We have investigated the effect of calcitonin gene-related peptide (CGRP) on non-adrenergic, non-cholinergic (NANC) excitatory transmission to the longitudinal muscle of the guinea-pig proximal colon. 2. In the presence of atropine (0.3 microM), guanethidine (5 microM), hexamethonium (100 microM) and indomethacin (3 microM), electrical field stimulation (EFS, 1 Hz, 0.3 ms for 10 s) produced tetrodotoxin-(300 nM)-sensitive contractions which were reduced by the combined administration of FK 888 (10 microM) and MEN 10,376 (0.3 microM), to block tachykinin NK1 and NK2 receptors, respectively. Thus, the EFS-induced NANC contractions are a tachykinin-mediated response. 3. CGRP, at concentrations higher than 0.1 nM, caused an increase in the electrically-evoked, NANC contractions in a concentration-dependent manner and at 10 nM produced a maximal effect (pEC50 = 9.20 +/- 0.17, n = 6). 4. 5-Hydroxytryptamine (5-HT, 1-100 nM) also caused an increase in the EFS-induced NANC contractions in a concentration-dependent manner and at 30 nM produced a maximal effect (pEC50 = 8.06 +/- 0.09, n = 4), but calcitonin (10-100 nM) failed to enhance the EFS-induced NANC responses. Moreover, a 5-HT4 receptor antagonist, DAU 6285 (3 microM) abolished the enhancing action of 5-HT (30 nM). 5. The combined administration of FK 888 (10 microM) plus MEN 10,376 (0.3 microM) abolished the enhancement of EFS-induced NANC contractions by CGRP (10 nM), but DAU 6285 (3 microM) had no effect on the enhancement. 6. Human CGRP8-37 (1 microM), a CGRP1 receptor antagonist had no effect on the submaximal enhancement of the electrically-evoked, NANC contractions by CGRP (1 nM).7. CGRP (30 nM) had no effect on contractions evoked by exogenous substance P (0.3-1 nM).8. These results indicate that in the guinea-pig proximal colon, CGRP produced an enhancement ofNANC contraction induced by EFS through prejunctional mechanisms and that the enhancement is mediated by the stimulation of non-CGRP1 receptors located on intramural tachykininergic neurones.Further, the possible contribution of 5-HT to the enhancing effect of CGRP appeared to be negligible.
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PMID:Calcitonin gene-related peptide (CGRP)-enhanced non-adrenergic non-cholinergic contraction of guinea-pig proximal colon. 758 58

Intracellular electrophysiological methods were used to examine the effects of 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), 4-amino-5-chloro-2-methoxy-N-(4-[1-azabicyclo[3,3,1]nonyl]) benzamide hydrochloride (renzapride), cis-4-amino-5-chloro-N[1-[3- (4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl[-2-methoxybenzamide monohydrate (cisapride) and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3- (1-methyl)ethyl-2-oxo-1 H-benzimidazole-1-carboxamidehydrochloride (BIMU 8) on noncholineric slow excitatory postsynaptic potentials (slow EPSPs) in myenteric afterhyperpolarization (AH) neurons of guinea pig ileum. 5-HT (0.01-1 microM) and 5-CT (0.001-0.1 microM) produced a concentration-dependent inhibition of slow EPSPs. The 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimidobutyl]piperazine (NAN-190) produced rightward shifts in 5-HT and 5-CT concentration-response curves; facilitation of slow EPSPs was never observed. 5-MeOT caused a depolarization and inhibited spike afterhyperpolarizations in a concentration-dependent manner but this effect was not blocked by the 5-HT3/5-HT4 receptor antagonist, tropisetron (1 microM). Renzapride (0.01-0.3 microM), cisapride (0.01-1.0 microM) and BIMU 8 (0.01-1.0 microM) did not change the membrane potential of any neuron tested. Renzapride and BIMU 8 did not change the amplitude of slow EPSPs. In 13 of 19 neurons cisapride did not change the amplitude of slow EPSPs; in 6 neurons cisapride (1 microM) reversibly inhibited the slow EPSP. Responses to substance P which mimicked the slow EPSP were not affected by cisapride.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of 5-HT1A and 5-HT4 receptor agonists on slow synaptic potentials in enteric neurons. 766 14

1. In the presence of atropine (0.2 microM) and indomethacin (2 microM), the effects of 5-hydroxytryptamine (5-HT) have been studied on electrically-evoked, neurogenic contractions of the guinea-pig proximal colon in vitro. 2. 5-HT, at higher concentrations than 1 nM, caused an increase in electrically (1 Hz, 0.3 ms, 160 mA)-evoked, atropine-resistant contractions in a concentration-dependent manner and at 30 nM produced a maximal effect (pEC50 value of 8.20 +/- 0.11, n = 6). The enhancing effects of 5-HT on the electrically evoked contractions were mimicked by alpha-methyl-5-HT (pEC50 value of 6.59 +/- 0.05, n = 6). 3. Both hexamethonium (100 microM) and spantide (10 microM), selective antagonists for nicotinic and tachykinin receptors respectively, significantly reduced the enhancement of the electrically evoked contractions by 5-HT (30 nM). 4. DAU 6285 (3 microM), a 5-HT4 receptor antagonist, abolished the enhancing action of 5-HT (30 nM), but metitepine (0.03 microM), a 5-HT1/5-HT2 receptor antagonist, ketanserin (0.01 microM), a 5-HT2 receptor antagonist, and ondansetron (1 microM), a 5-HT3 receptor antagonist, had no effect on the enhancement. The enhancing effects of alpha-methyl-5-HT (1 microM) were also abolished by DAU 6285 (3 microM). 5. Both 5-HT (30 nM) and alpha-methyl-5-HT (1 microM) had no effect on contractions to exogenous substance P (0.15-0.3 nM). 6. These results indicate that in the guinea-pig proximal colon, 5-HT produced an enhancement of atropine-resistant neurogenic contraction induced by electrical field stimulation through pre-junctional mechanisms and that the enhancement is mediated by the stimulation of 5-HT4 receptors located on intramural preganglionic cholinergic neurones and tachykininergic neurones.
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PMID:An enhancing effect of 5-hydroxytryptamine on electrically evoked atropine-resistant contraction of guinea-pig proximal colon. 771 32

1. The aim of this study was to characterize the receptors mediating the atropine-resistant neurogenic contraction to 5-hydroxytryptamine (5-HT) in the longitudinal muscle of the guinea-pig proximal colon and to determine the type of tachykinin receptors involved in the contractile response to 5-HT by the use of selective antagonists. 2. In the presence of atropine (0.3 microM), guanethidine (5 microM), hexamethonium (100 microM), ketanserin (0.1 microM) and indomethacin (3 microM), 5-HT (0.01-3 microM) produced concentration-dependent neurogenic contractions of colonic strips and at 0.3 microM produced a maximal effect (pEC50 = 7.39 +/- 0.09, n = 18). The 5-HT4 receptor stimulant, 5-methoxytryptamine (5-MeOT, 0.03-10 microM) also produced neurogenic contractions with similar maximum effect to those of 5-HT (pEC50 = 6.89 +/- 0.16). 3. The 5-HT4 receptor antagonist, DAU 6285 (3 microM) shifted the concentration-response curves to both 5-HT and 5-MeOT to the right without significant depression of the maximum, but the 5-HT1/5-HT2 receptor antagonist, metitepine (0.1 microM) and the 5-HT3 receptor antagonist, ondansetron (0.3 microM) had no effect on the control curves to 5-HT and 5-MeOT. 4. The selective NK1 receptor antagonist, FK 888 (1 microM) markedly attenuated the contractions to 5-HT and 5-MeOT. In contrast, the selective NK2 receptor antagonist, SR 48968 (10 nM) and the selective NK3 receptor antagonist, SR 142801 (10 nM) had no effect on the contractions to 5-HT and 5-MeOT. 5. These results indicate that the 5-HT-induced atropine-resistant neurogenic contraction of guinea-pig proximal colon is due to activation of 5-HT4 receptors, presumably located on excitatory motor neurones, innervating the longitudinal muscle. The contraction evoked by activation of the 5-HT4 receptors is mediated primarily via NK1 receptors but not NK2 or NK3, suggesting that the 5-HT4 receptor-mediated contraction is evoked indirectly via tachykinin release from tachykinin-releasing excitatory neurones.
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PMID:Investigation into the 5-hydroxytryptamine-induced atropine-resistant neurogenic contraction of guinea-pig proximal colon. 873 67

The pathways and possible transmitters involved in the contractile response to selective 5-HT3 and 5-HT4 receptor stimulation in the guinea-pig proximal colon were studied. In the presence of methysergide, 5-HT induced contractions, yielding a biphasic concentration-response curve that was changed into a monophasic curve in the presence of the 5-HT3 receptor antagonist, granisetron (1 microM) (low-affinity phase blocked), or the 5-HT4 receptor antagonist, SB 204070 ((1-butyl-4-piperidinyl methyl)-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate) (10 nM) (high-affinity phase blocked) combination of the two antagonists abolished the contraction to 5-HT. The effectiveness and selectivity of both antagonists was confirmed by testing them against contractions in response to the 5-HT3 receptor-selective agonist, 2-methyl-5-HT, and the 5-HT4 receptor-selective agonist, 5-methoxytryptamine. Hexamethonium (100 microM) did not affect the 5-HT3 receptor-mediated contractions, whereas tetrodotoxin (0.3 microM) caused only slight inhibition. Both in the absence and presence of tetrodotoxin, atropine (0.3 microM) inhibited the 5-HT3 receptor-mediated contractions. Hence, the contractions to 5-HT are partly mediated by 5-HT3 receptors that are localized on the nerve endings of the motor neurons. Hexamethonium halved the 5-HT4 receptor-mediated contractions, whereas tetrodotoxin abolished them. The 5-HT4 receptor-mediated contractions were inhibited by atropine (0.3 microM). Thus, the 5-HT4 receptors seem to be localized in the soma of the motor neurons; they also occur on interneurons. The remaining contractions induced by 5-HT3 and 5-HT4 receptor stimulation in the presence of atropine were almost completely inhibited by the tachykinin NK1 receptor antagonist, CP 96345 ((2S,3S)-cis-2-(diphenyl methyl)-N-[(2-methoxy phenyl)-methyl]-1-azabicyclo-[2.2.2]-octan-3-amine) (0.1 microM). CP 96345 also abolished or strongly inhibited contractions in response to substance P (10 nM) and to neurokinin A (30 nM), but neither granisetron nor SB 204070 affected them. Hence, stimulation of either 5-HT3 or 5-HT4 receptors induced contractions that are partially mediated by acetylcholine, and partially by a tachykinin NK1 receptor-stimulating neurotransmitter, probably substance P and/or neurokinin A.
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PMID:5-HT3 and 5-HT4 receptors and cholinergic and tachykininergic neurotransmission in the guinea-pig proximal colon. 884 Jan 29

Interaction between the 5-HT4 receptor and cholinergic-dependent and -independent contraction of the rat oesophageal muscularis mucosae was determined. Substance P- (in the presence of atropine) and carbachol-precontracted tissue was relaxed by tryptamines and the substituted benzamides with the following rank order of potency: 5-HT > 5-methoxytryptamine > cisapride > (R)-zacopride > lintopride > metoclopramide, consistent with 5-HT4 receptor activation. The response to 5-HT was not antagonized by tetrodotoxin, methysergide or ondansetron; but was shifted to the right by GR113808 ([1-[2-[methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-1-H- indole-3-carboxylate) in substance P- and carbachol-precontracted tissue, confirming 5-HT4-mediated relaxation. This study shows for the first time that although 5-HT4 receptors are involved in the modulation of cholinergic neurotransmission they can also act independently of this system modulating tachykinergic responsiveness.
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PMID:Post-synaptic 5-HT4 receptor modulation of tachykinergic excitation of rat oesophageal tunica muscularis mucosae. 912 43

1. In the Fisher 344 rat, tachykinins have been shown to cause the release of 5-hydroxytryptamine (5-HT) from airway mast cells, which then causes direct smooth muscle activation as well as the release of acetylcholine from cholinergic nerves. The aim of the present study was to examine the modulatory effects of 5-HT receptors on the neurokinin A (NKA)-induced release of endogenous 5-HT and airway smooth muscle contraction in the isolated Fisher 344 rat trachea. 2. The selective 5-HT2 receptor antagonist ketanserin (0.1 microM) produced an almost complete inhibition of the contractions caused by NKA (n=4, P<0.0001, two-way ANOVA), and a significant rightward shift of the concentration-response curve to 5-HT (n=8, P<0.001, two-way ANOVA). 3. The partial agonist for 5-HT1A receptors, 8-OH-DPAT (1 microM), and the full agonist for 5-HT1 receptors, 5-CT (0.3 microM), potentiated the submaximal contractions induced by the 5-HT2 receptor agonist alpha-methyl-5-HT (0.1 microM) (n=4; P<0.005 and P<0.05, respectively). 8-OH-DPAT (1 microM), as well as the 5-HT1A receptor antagonists pMPPI, SDZ 216525 and NAN-190 (0.1 microM each), caused significant inhibition of the tracheal contractions induced both by NKA (10 nM-3 microM) and 5-HT (10 nM-10 microM) (n=4-10). This suggests that activation of 5-HT1A receptors potentiates the 5-HT2 receptor-mediated contractions. 4. SDZ 216525 (0.1 microM) significantly reduced the maximal contraction produced by 1 microM NKA (n=10, P< 0.001), without affecting the release of endogenous 5-HT. These data rule out the involvement of a 5-HT1A receptor-mediated positive feedback mechanism of the 5-HT release from mast cells. 5. Even in the presence of atropine (1 microM), 8-OH-DPAT (1 microM) further reduced the maximal NKA-induced contraction (n=4, P<0.0001), while the contractions of the rat isolated trachea induced by electrical field stimulation and the concentration-response curve to carbachol were unaffected by pMPPI (0.1 microM), SDZ 216525 (0.1 microM), NAN-190 (0.1 microM) and 8-OH-DPAT (1 microM) (n=4-6). These data demonstrate that the 5-HT1A receptor-mediated potentiation of contractile responses is not due to nonspecific inhibition of airway smooth muscle contraction or to modulation of postganglionic nerve activation. 6. The selective 5-HT1B/1D receptor antagonist GR 127935, the selective 5-HT3 receptor antagonist tropisetron and the selective 5-HT4 receptor antagonists SB 204070 and GR 113808 (0.1 microM each) had no effect on the concentration-response curve for NKA (n=6-10), ruling out the involvement of 5-HT1B/1D, 5-HT3 and 5-HT4 receptors. 7. The alpha-adrenoreceptor antagonist phentolamine (1 microM) had no effect on the 5-HT-induced contractions (n=4), ruling out the involvement of alpha-adrenoreceptors. 8. In conclusion, the tachykinin-induced contraction of the F334 rat isolated trachea is mediated by the stimulation of 5-HT2 receptors. Activation of 5-HT1A receptors located on airway smooth muscle potentiates the direct contractile effects of 5-HT2 receptor activation. The 5-HT1B/1D, 5-HT3 and 5-HT4 receptors are not involved in the NKA-induced contraction of rat airways.
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PMID:Modulation by 5-HT1A receptors of the 5-HT2 receptor-mediated tachykinin-induced contraction of the rat trachea in vitro. 960 63

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