Tachykinin NK 2 receptors and enhancement of cholinergic transmission in the inflamed rat colon: an in vivo motility study (original) (raw)
Related papers
British Journal of Pharmacology, 1998
1 The role of endogenous tachykinins on guinea-pig colonic propulsion was investigated by using potent and selective tachykinin NK 1 and NK 2 receptor antagonists. Colonic propulsion and contractions were determined by means of a balloon-catheter device, inserted into the rectum of guanethidine (68 mmol kg 71 , s.c., 18 and 2 h before)-pretreated, urethane-anaesthetized guinea-pigs. Propulsion of the device (dynamic model) was determined by measuring the length of the catheter expelled during 60 min ®lling of the balloon (¯ow rate 5 ml min 71 ). 2 In control conditions the tachykinin NK 1 receptor antagonist SR 140333 (1 mmol kg 71 , i.v.) did not aect either colonic propulsion or the amplitude of contractions. The tachykinin NK 2 receptor antagonists MEN 10627 and MEN 11420 (1 mmol kg 71 , i.v.) increased colonic propulsion at 10 min (+120% and 150%, respectively) but at 60 min the eect was signi®cant only for MEN 10627 (+84%). SR 48968 (1 mmol kg 71 , i.v.) did not signi®cantly enhance the colonic propulsion. None of these tachykinin NK 2 receptor antagonists modi®ed the amplitude of colonic contractions. In contrast, both atropine (6 mmol kg 71 , i.v., plus infusion of 1.8 mmol h 71 ) and hexamethonium (55 mmol kg 71 , i.v., plus infusion of 17 mmol h 71 ) abolished propulsion (81% and 87% inhibition, respectively) and decreased the amplitude of contractions (68% inhibition for either treatment).
European Journal of Pharmacology, 1993
The effects of three tachykinin NK 1 receptor antagonists and a tachykinin NK 2 receptor antagonist against substance P-induced contractions of the guinea-pig proximal colon longitudinal muscle were investigated. Atropine, tetrodotoxin and phosphoramidon did not affect the concentration-response curve for substance P (pECs0 = 7.8). The tachykinin NK1 receptor antagonist, 2S,3S-cis-CP 96345, competitively inhibited the contractions due to substance P (pA 2 = 8.5; constrained pA 2 = 8.9), but at higher concentrations (>_ 3 × 10 -7 M), 2S,3S-cis-CP 96345 also depressed the concentration-response curve for methacholine. The species-selective tachykinin NK~ receptor antagonists, WIN 51708 and WIN 62577 (both 1 × 10 6 M), and the tachykinin NK 2 receptor antagonist, SR 48968 (3 × 10 -7 M), had no effect. It is concluded that substance P induces contractions through the stimulation of tachykinin NK 1 receptors on the smooth muscle cells. In this preparation, tachykinin NK 2 receptors do not seem to be involved in the contractile action of substance P.
British Journal of Pharmacology, 1992
1 The effect of newly developed, receptor-selective tachykinin antagonists (GR 71,251 for NK1 receptors, MEN 10,376 and L 659,877 for NK2 receptors) on noncholinergic transmission to the circular muscle of the guinea-pig ileum has been investigated. 2 In circular muscle strips of the ileum, electrical field stimulation in the presence of atropine (2 jM) and apamin (0.1 jAM) evoked a complex motor response. The tonic primary contraction in this response was reduced by GR 71,251 (10 jM) and MEN 10,376 (3-10 I1M) but not by L 659,877 (up to 10 jM). The presence of apamin was necessary in this experimental arrangement to unmask an atropine-resistant primary contraction, sensitive to tachykinin antagonists. The motor response was abolished by tetrodotoxin.
British Journal of Pharmacology, 1994
The aim of this study was the pharmacological characterization of tachykinin NKI and NK2 receptors mediating contraction in the circular muscle of the guinea-pig ileum and proximal colon. The action of substance P (SP), neurokinin A (NKA) and of the synthetic agonists [SarlSP sulphone, [Glp6,Pro9]SP(6-1I) (septide) and [PAla8]NKA(4-l0) was investigated. The affinities of various peptide and nonpeptide antagonists for the NKI and NK2 receptor was estimated by use of receptor selective agonists. 2 The natural agonists, SP and NKA, produced concentration-dependent contraction in both preparations. EC50 values were 100 pM and 5 nM for SP, 1.2 nM and 19 nm for NKA in the ileum and colon, respectively. The action of SP and NKA was not significantly modified by peptidase inhibitors (bestatin, captopril and thiorphan, 1 gM each). 3 Synthetic NKI and NK2 receptor agonists produced concentration-dependent contraction of the circular muscle of the ileum and proximal colon. EC5, values were 83 pM, 36 pM and 10 nM in the ileum, 8 nM, 0.7 nM and 12 nM in the colon for [SarlSP sulphone, septide and [PAla8]NKA(4-10), respectively. The pseudopeptide derivative of NKA(4-10), MDL 28,564 behaved as a full or near-to-full agonist in both preparations, its EC50s being 474 nM and 55 nM in the ileum and colon, respectively. 4 Nifedipine (1 pM) abolished the response to septide and [SarlSP sulphone in the ileum and produced a rightward shift and large depression of the response in the colon. The response to [pAla']NKA(4-10) was abolished in the ileum and largely unaffected in the colon. 5 The NK1 receptor antagonists, (±)-CP 96,34, FK 888 and GR 82,334 competitively antagonized the response to septide and [SarISP sulphone in both preparations without affecting that to LPAla8]NKA(4-10). In general, the NK1 receptor antagonists were significantly more potent toward septide than [SarlSP sulphone in both preparations. 6 The NK2 receptor antagonists, GR94,800 and SR48,968 selectively antagonized the response to [PAla8]NKA(4-I0) without affecting that to [SarlSP sulphone or septide in the ileum and colon. SR48,968 produced noncompetitive antagonism of the response to the NK2 receptor agonist in the ileum and competitive antagonism in the colon. 7 MEN 10,376 and the cyclic pseudopeptide MEN 10,573 antagonized in a competitive manner the response to [PAla8]NKA(4-I0) in the ileum and colon. While MEN 10,573 was equipotent in both preparations, MEN 10,376 was significantly more potent in the colon than in the ileum. MEN 10,376 was also effective against septide in both preparations, without affecting the response to [SarlSP sulphone. MEN 10,573 antagonized the response to [SarlSP sulphone and septide in both preparations, pKB values against septide being intermediate, and significantly different from, those measured against [LAla8]NKA(4-10) and [SarlSP sulphone. 8 These findings show that tachykinin NK, and NK2 receptors mediate contraction of the circular muscle of the guinea-pig ileum and colon. In both preparations NKI receptor antagonists display higher apparent affinity when tested against septide than [SarlSP sulphone. These findings are compatible with the proposed existence of NK1 receptor subtypes in guinea-pig, although alternative explanations (e.g. agonist binding to different epitopes of the same receptor protein) cannot be excluded at present. Furthermore, an intraspecies heterogeneity of the NK2 receptor in the circular muscle of the guinea-pig ileum and colon is suggested.
Journal of Autonomic Pharmacology, 1997
This study aimed to assess the eect of cyclopiazonic acid (CPA), an inhibitor of sarcoplasmic reticulum calcium (Ca) pump, against contractile responses produced by selective tachykinin NK 1 and NK 2 receptor agonists, [Sar 9 ]substance P (SP) sulfone and [bAla 8 ]neurokinin A (NKA) (4±10), respectively, on the circular muscle of guinea-pig colon. All experiments were performed in the presence of atropine (1 mM) and indomethacin (10 mM). 2 In organ bath experiments, a submaximally equieective concentration of the two agonists (10 nM) was selected: [Sar 9 ]SP sulfone (10 nM) produced a biphasic contraction, the two amplitudes averaging 75 + 2 and 43 + 3% of the maximal response to KCl (80 mM) at 1 and 15 min from application of the agonist, respectively. CPA (3 mM for 60 min) slightly reduced the phasic response to [Sar 9 ]SP sulfone (16 + 4% inhibition) and markedly suppressed the tonic component (89 + 3% inhibition). 3 The contraction produced by [bAla 8 ]NKA (4±10) (10 nM) was more sustained than that induced by the NK 1 receptor agonist: it averaged 69 + 5 and 73 + 4% of the response to KCl at 1 and 15 min from application of the agonist, respectively. CPA slightly and evenly depressed the response to [bAla 8 ]NKA (4±10) (18 + 7 and 21 + 5% inhibition at 1 and 15 min). 4 In the presence of tachykinin NK 1 and NK 2 receptor antagonists (SR 140333 and MEN 10627, respectively, 1 mM each) and of L-nitroarginine (100 mM), KCl (40 mM) produced a distinct phasic and tonic contraction which was suppressed by 1 mM nifedipine. CPA (3 mM) did not aect the phasic contraction to KCl but abolished the tonic component of the response. 5 In the presence of 1 mM nifedipine, the response to [bAla 8 ]NKA (4±10) was slightly depressed (32 + 6% inhibition) in its early component only, while the response to [Sar 9 ]SP sulfone was abolished. CPA produced a slight inhibition (15 + 9 and 33 + 10% at 1 and 15 min, respectively) of the nifedipine-resistant response to [bAla 8 ]NKA (4±10), an eect similar to that observed in the absence of nifedipine. Therefore, a large part of the response to [bAla 8 ]NKA (4±10) persisted in the presence of both CPA and nifedipine. 6 In the sucrose gap, a prolonged superfusion with [Sar 9 ]SP sulfone (0.1 mM for 5 min) produced sustained depolarization with superimposed spikes and contraction. CPA (3 mM) produced transient depolarization and contraction. In the presence of CPA, the initial responses (depolarization, spikes and contraction) to [Sar 9 ]SP sulfone were unaected but the sustained component of contraction was absent; the latter eect was accompanied by a suppression of spikes while the sustained depolarization was present. 7 We conclude that, during sustained depolarization produced by the NK 1 receptor agonist, blockade of the sarcoplasmic reticulum Ca pump by CPA produces a faster Ca-dependent inactivation of Ca channels, thereby eliminating spikes and abolishing the tonic component of contraction. Ca mobilization/reuptake from a CPA-sensitive store seems to be of minor importance for regulating the NK 2 receptor-mediated contractile responses.
Tachykinin receptors and intestinal motility
Canadian Journal of Physiology and Pharmacology, 1997
Substance P (SP) and neurokinin A (NKA) are synthesized by enteric cholinergic motorneurons that project to the longitudinal and circular muscle of the mammalian intestine. Thus, acetylcholine, SP, and NKA are the excitatory neuromuscular transmitters in the intestine. Tachykinin NK 1 and NK 2 receptors are expressed by smooth muscle cells in most regions of the intestine: the corelease of SP and NKA from nerves thus realizes paradigms of tachykininergic cotransmission. Examples have been found in which a cooperative model can be applied to account for the action of SP-NKA acting at NK 1 and NK 2 receptors (e.g., circular muscle of guinea-pig duodenum), as well as examples in which the message produced by activation of the two receptors diverges sharply in producing responses that have a markedly different time course and use different effector systems (e.g., circular muscle of guinea-pig colon). NK 3 receptors are expressed on both excitatory and inhibitory motor neurons: indirect contractions (via release of acetylcholine and tachykinins) and relaxations (via release of nitric oxide) can be evoked in the gut by selective stimulation of NK 3 receptors. Although a role of NK 3 receptors in certain enteric reflexes has been evidenced, the importance of this system in mediating hexamethonium-resistant enteric transmission appears less important than previously speculated.
Tachykinins and tachykinin receptors in the gut, with special reference to NK2 receptors in human
Autonomic Neuroscience, 2006
Tachykinins (TKs), substance P (SP), neurokinin A (NKA) and B (NKB) are important peptide modulators of intestinal motility in animal species studied so far, including humans. Modulation of motility by TKs can occur at various levels, since these peptides are expressed in cholinergic excitatory motor neurons projecting to both circular and longitudinal muscle, interneurons, and intramural and extramural sensory neurons. The effects of SP, NKA and NKB are preferentially mediated through the stimulation of NK1, NK2 and NK3 receptors, respectively; however, the selectivity of natural TKs for their preferred receptors is relative. In addition, SP and NKA are expressed in similar quantities in the human intestine and adequate stimuli can release similar amount of these TKs from enteric nerves. Furthermore, a single anatomical substrate can express more than one TK receptor type, so that the blockade of a single receptor type may not reveal functional effects in integrated models of motility. In isolated human small intestine and colon circular muscle strips, both NK1 and NK2 receptors mediate contractile effects. Indeed, in the human small intestine, smooth muscle electrical and motor events induced by electrical field stimulation (EFS) can involve either or both NK1 and NK2 receptors or these latter receptors predominantly, depending on the experimental conditions. In contrast, in the human colonic smooth muscle, only the NK2 receptor-mediated component of the response to EFS is prominent and some evidence would suggest that this component is the main excitatory motor mechanism at this level. Furthermore, a NK2 receptor-mediated secretory component in the human colonic mucosa has been recently demonstrated. Thus, it could be speculated that the blockade of both NK1 and NK2 receptors will be necessary to antagonise motor effects induced by exogenous administration or endogenous release of TKs in the small intestine, whereas the blockade of the NK2 receptors would be sufficient to disrupt physiological motor and, possibly, secretory activity at the colonic level. Available evidence indicates that, in healthy volunteers, the infusion of NKA (25 pmol/kg/min i.v.) stimulated small intestine motility and precipitated a series of intestinal and non-intestinal adverse events. Nepadutant (8 mg i.v.), a selective NK2 receptor antagonist, antagonised small intestine motility induced by NKA and prevented associated intestinal adverse events. In another study, the same dose of nepadutant increased colo-rectal compliance during isobaric balloon distension in healthy volunteers pretreated with a glycerol enema, disclosing a NK2 receptor-mediated component in the regulation of colonic smooth muscle tone. However, the prolonged blockade of NK2 receptors by nepadutant (16 mg i.v. b.i.d. for 8days) did not affect bowel habits, neither in term of movements nor of stool consistency. Altogether, these results indicate that, even when there is a significant redundance in the effects of TKs and in the role of their receptors, the selective blockade of tachykinin NK2 receptors can have functional consequences on human intestinal motility and perception, but this can occur without the disruption of the physiological functions. D
Acta Physiologica Scandinavica, 1994
We have studied the effect of a novel tachykinin, neuropeptide gamma (NP gamma) on small intestinal motility in the rat. Experiments were done in vitro on longitudinal muscle strips of duodenum, and in vivo on the migrating myoelectric complex (MMC) of the small intestine. In vitro, contractile effects of NP gamma were compared with those of a selective neurokinin 1 (NK1) receptor agonist, substance P methyl ester (SPME), and a selective neurokinin 2 (NK2) receptor agonist, Nle10-NKA(4-10)(NleNKA). NP gamma, SPME and NleNKA caused concentration-dependent contractions (P < 0.001). NP gamma was eight-fold more potent than NleNKA, and 118-fold more potent than SPME. Contractile responses to NP gamma were reduced by hexamethonium (P < 0.01) and atropine (P < 0.05). The non-selective NK receptor antagonist spantide I only slightly reduced the contractile response to NP gamma, as did the selective NK1 antagonist GR 82,334, and the selective NK2 antagonist L-659,877 and MEN 10,376. In vivo, effects of NP gamma on the MMC were compared with those of the natural tachykinins substance P (SP) and neurokinin A (NKA). NP gamma disrupted the MMC and induced irregular spiking in a dose-dependent manner from 25 to 100 pmol kg-1 min-1 i.v. (P < 0.05). The effect of NP gamma was more prominent than that of NKA at equal doses, while SP had no effect. Our findings show that NP gamma exerts potent stimulatory effects on small intestinal motility, most likely mediated directly via distinct NK receptors on smooth muscle cells, but also indirectly via a cholinergic link.