Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The study aimed to establish the possible role of tachykinins as mediators of atropine-resistant reflex contractions evoked by balloon distension in the proximal duodenum of urethane-anesthetized, guanethidine (34 mumol/kg s.c.)-pretreated rats. Distension of the balloon with a small amount (0.2-0.3 ml) of saline induced the appearance of phasic rhythmic contractions (about 11 mmHg in amplitude) which were promptly suppressed by either atropine (3 mumol/kg i.v.) or hexamethonium (28 mumol/kg i.v.). Despite the continuous i.v. infusion of atropine (2 mumol/h), low-amplitude rhythmic phasic contractions recovered, which were promptly suppressed by hexamethonium, to indicate the involvement of an atropine-resistant excitatory reflex. The amplitude of these atropine-resistant contractions was increased to about 4-5 mmHg by further distension of the balloon (0.4-0.6 ml) : under these conditions, the atropine-resistant contractions undergo a progressive fading. The fading was prevented by i.v. administration of the nitric oxide (NO) synthase inhibitor, L-nitroarginine methyl ester (L-NAME, 55 mumol/h), to provide a suitable baseline (amplitude of contractions was 7-8 mmHg) for studying the effect of tachykinin receptor antagonists. I.v. administration of the selective tachykinin NK2 receptor antagonists, MEN 10,627 (10-100 nmol/kg) and SR 48968 (100-300 nmol/kg) or of the selective NK1 antagonist SR 140333 (100 nmol/kg), at doses which do not affect the duodenal contractions induced by acetylcholine (5.5 mumol/kg i.v.), produced a prompt and long lasting suppression of the atropine-resistant reflex duodenal contractions produced by balloon distension in urethane-anesthetized rats, whilst SR-48965 (300 nmol/kg), the enantiomer of SR-48968 devoid, of NK2 receptor blocking activity, was without effect. I.v. administration of the selective NK1 receptor agonists [Sar9] substance P sulfone and septide or of the NK2 receptor selective agonist, [beta Ala8] neurokinin A(4-10) produced dose-dependent contractions of the duodenum. SR 140333 (100 nmol/kg i.v.) selectively antagonized the duodenal contractions produced by [Sar9] substance P sulfone and septide without affecting those produced by [beta Ala8] neurokinin A(4-10). On the other hand, MEN 10,627 (30-100 nmol/kg i.v.) and SR 48968 (100-300 nmol/kg i.v.) but not SR 48965 (300 nmol/kg i.v.) antagonized, at a comparable extent, duodenal contractions induced by both the selective NK2 and NK1 receptor agonists. We conclude that endogenous tachykinins are involved in mediating atropine-resistant reflex contractions evoked by distension of the rat duodenum in vivo: both NK1 and NK2 receptors are activated by endogenous ligands to produce NANC contractions of rat duodenum in vivo. However, the contractile response to i.v. administered NK1 receptor agonists, [Sar9] substance P sulfone and septide, may involve the release of mediators producing smooth muscle contraction via NK2 receptors.
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PMID:Tachykinin receptors mediate atropine-resistant rat duodenal reflex contractions in vivo. 887 63

1. This study investigated the possibility that tachykinins relax the guinea-pig isolated trachea by releasing nitric oxide (NO) from the epithelium. The types of tachykinin receptor mediating both relaxation and contraction of the trachea were also studied. Isometric tension was recorded in isolated tracheal tube preparations precontracted with acetylcholine (10 microM) in which compounds were administered intraluminally in the presence of phosphoramidon and indomethacin (both 1 microM) and the tachykinin NK2 receptor antagonist, SR 48,968 ((S)-N-methyl-N[4-(4-acetyl amino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide), 0.1 microM). 2. In the presence of the inactive enantiomer of an NO-synthase inhibitor, NG-monomethyl-D-arginine (D-NMMA, 100 microM), substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and the selective NK1 receptor agonist, [Sar9, Met(O2)11]-SP, (0.1-10 nM) relaxed tracheal tube preparations. This relaxation was changed into a contraction by pretreatment with the NO-synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA, 100 microM). The effect of L-NMMA on SP- and [Sar9, Met(O2)11]-SP-induced responses was reversed by L-arginine (L-Arg, 1 mM), but not by D-Arg (1 mM). After removal of the epithelium SP, NKA and NKB and [Sar9, Met(O2)11]-SP (0.1-10 nM) evoked contractile responses in the presence of either L-NMMA (100 microM) or D-NMMA (100 microM). The effects of SP and [Sar9, Met(O2)11]-SP obtained in the presence of another NO-synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) or its inactive enantiomer, NG-nitro-D-arginine methyl ester (D-NAME, 100 microM) were similar to those observed with L-NMMA or D-NMMA, respectively. 3. The selective NK1 receptor agonist, [pGlu6, Pro9]-SP(6-11) (septide, 0.1-10 nM) evoked contractile responses of tracheal tube preparations in the presence of either D-NMMA (100 microM) or L-NMMA (100 microM). The log concentration-response curve to septide obtained in the presence of L-NMMA was similar to that obtained in the presence of D-NMMA. [Sar9, Met(O2)11]-SP (0.1-10 nM) relaxed tracheal tube preparations precontracted with septide (1 microM), whereas septide (0.1 nM-1 microM) further contracted tracheal tube preparations precontracted with [Sar9, Met(O2)11]-SP (1 microM). 4. Relaxant and contractile responses evoked by SP, NKA, NKB and by [Sar9, Met(O2)11]-SP (0.1-10 nM) were not affected by a combination of the histamine H1 (pyrilamine, 1 microM) and H2 (cimetidine, 1 microM) receptor antagonists, but were abolished by the tachykinin NK1 receptor antagonist, CP-99,994 ((2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine, 1 microM), though not by its inactive enantiomer CP-100,263 (1 microM). Contractile responses evoked by septide (10 nM and 1 microM) were also abolished by CP-99,994 (1 microM) but not by CP-100,263 (1 microM). 5. These results demonstrate that tachykinins relax guinea-pig tracheal tube preparations by releasing NO via the stimulation of epithelial NK1 receptors by a mechanism independent of histamine release. The NK1 receptor type involved is sensitive to SP, NKA, NKB and [Sar9, Met(O2)11]-SP but not to septide, and is pharmacologically distinct from the NK1 receptor that mediates contraction, which is stimulated by all the agonists, including septide.
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PMID:Evidence that tachykinins relax the guinea-pig trachea via nitric oxide release and by stimulation of a septide-insensitive NK1 receptor. 888 25

Inhalation of cold air in guinea pigs increases total pulmonary resistance (RL), an effect that is mediated by kinins and tachykinins. Bronchoconstriction induced by bradykinin (BK) inhalation in guinea pigs is markedly inhibited by nitric oxide (NO) release from the airway epithelium. We investigated whether endogenous NO modulates the increase in RL induced by inhalation of cold air. In anesthetized and artificially ventilated guinea pigs pretreated with atropine, cold-air inhalation (13 degrees C in the trachea) for 5 min did not increase RL. Pretreatment with intravenous N(G)-nitro-L-arginine methyl ester (L-NAME) (but not with its inactive enantiomer, D-NAME) increased RL, an effect reversed by L-Arg. The increase in RL induced by cold air after L-NAME was abolished by the tachykinin NK2-receptor antagonist SR 48968 or the kinin B2-receptor antagonist, HOE 140. After administration of SR 48968, inhalation of cold air reduced baseline airway tone. However, after HOE 140, cold-air inhalation did not affect baseline airway tone. L-NAME exaggerated the bronchoconstriction induced by BK. However, L-NAME did not affect capsaicin-induced bronchoconstriction. BK increased cyclic guanosine monophosphate (cGMP) levels in strips of guinea pig trachealis muscle in vitro, whereas the selective tachykinin NK2-receptor agonist [betaAla8]neurokinin A (4-10) was without effect. The present data suggest that bronchoconstriction induced by cold-air inhalation and mediated by kinin and tachykinin release is inhibited by endogenous NO, and that kinins, but not tachykinins or cold air alone, release bronchorelaxant NO.
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PMID:Endogenous nitric oxide inhibits bronchoconstriction induced by cold-air inhalation in guinea pigs: role of kinins. 947 71

1 The characterization of the B1 kinin receptor, and some mediators involved in the inflammatory response elicited by intrathoracic (i.t.) administration of des-Arg9-bradykinin (BK) in the mouse model of pleurisy, was investigated. 2 An i.t. injection of des-Arg9-BK (10-100 nmol per site), a selective B1 agonist, caused a significant and dose-related increase in the vascular permeability observed after 5 min, which peaked at 1 h, associated with an increase in cell influx, mainly neutrophils, and, to a lesser extent, mononuclear cell influx, peaking at 4 h and lasting for up to 48 h. The increase in fluid leakage caused by des-Arg9-BK was completely resolved 4 h after peptide injection. I.t. injection of Lys-des-Arg9-BK (30 nmol per site) caused a similar inflammatory response. 3 Both the exudation and the neutrophil influx elicited by i.t. injection of des-Arg9-BK were significantly antagonized (P<0.01) by an i.t. injection of the selective B1 antagonists des-Arg9-[Leu8]-BK (60 and 100 nmol per site) or des-Arg9-NPC 17731 (5 nmol per site), administered in association with des-Arg9-BK (P<0.01), or 30 and 60 min before the cellular peak, respectively. In contrast, an i.t. injection of the B2 bradykinin selective receptor antagonist Hoe 140 (30 nmol per site), at a dose which consistently antagonized bradykinin (10 nmol per site)-induced pleurisy, had no significant effect on des-Arg9-BK-induced pleurisy. 4 An i.t. injection of the selective tachykinin receptor antagonists (NK1) FK 888 (1 nmol per site), (NK2) SR 48968 (20 nmol per site) or (NK3) SR 142801 (10 nmol per site), administered 5 min before pleurisy induction, significantly antagonized neutrophil migration caused by i.t. injection of des-Arg9-BK. In addition, FK 888 and SR 142801, but not SR 48968, also prevented the influx of mononuclear cells in response to i.t. injection of des-Arg9-BK (P<0.01). However, the NK3 receptor antagonist SR 142801 (10 nmol per site) also significantly inhibited des-Arg9-BK-induced plasma extravasation. An i.t. injection of the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP8-37 (1 nmol per site), administered 5 min before pleurisy induction, inhibited des-Arg9-BK-induced plasma extravasation (P<0.01), without significantly affecting the total and differential cell migration. 5 The nitric oxide synthase inhibitors L-NOARG and L-NAME (1 pmol per site), administered 30 min beforehand, almost completely prevented des-Arg9-BK (i.t.)-induced neutrophil cell migration (P<0.01), and, to a lesser extent, mononuclear cell migration (P<0.01). The D-enantiomer D-NAME had no effect on des-Arg9-BK-induced pleurisy. At the same dose range, L-NOARG and L-NAME inhibited the total cell migration (P<0.01). L-NAME, but not L-NOARG caused significant inhibition of des-Arg9-BK-induced fluid leakage. Indomethacin (1 mg kg(-1), i.p.), administered 1 h before des-Arg9-BK (30 nmol per site), inhibited the mononuclear cell migration (P<0.05), but, surprisingly, increased the neutrophil migration at 4 h without interfering with plasma extravasation. The administration of terfenadine (50 mg kg(-1), i.p.), 30 min before des-Arg9-BK (30 nmol per site), did not interfere significantly with the total cell migration or with the plasma extravasation in the mouse pleurisy caused by i.t. injection of des-Arg9-BK. 6 Pretreatment of animals with the lipopolysaccharide of E. coli (LPS; 10 microg per animal, i.v.) for 24 h did not result in any significant change of the inflammatory response induced by i.t. injection of des-Arg9-BK compared with the saline treated group. However, the identical treatment of mice with LPS resulted in a marked enhancement of des-Arg9-BK induced paw oedema (P<0.01). 7 In conclusion, we have demonstrated that the inflammatory response induced by i.t. injection of desArg9-BK, in a murine model of pleurisy, is mediated by stimulation of constitutive B1 receptors. (These responses are largely mediated by release of neuropeptides such as substanceP or CGRP and also by NO, but products derived from cyclo-oxygenase pathway and histamine seem not to be involved. Therefore, these results further support the notion that the B1 kinin receptor has an important role in modulating inflammatory responses, and it is suggested that selective B1 antagonists may provide therapeutic benefit in the treatment of inflammatory and allergic conditions.
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PMID:Characterization of the receptor and the mechanisms underlying the inflammatory response induced by des-Arg9-BK in mouse pleurisy. 948 17

In the present study, it was demonstrated that SP, neurokinin A (NKA), neurokinin B (NKB), SP methyl ester (SPME), [Ala5, beta-Ala8]-alpha-neurokinin fragment 4-10 (AANF) at 10(-8) M all caused contraction in non-contracted endothelium-intact arteries. SP- and SPME-induced contraction were reduced by removal of endothelium. All the peptides with the exception of AANF induced transient relaxation in the precontracted arteries. The relaxation were attenuated by removal of endothelium. The potency orders for endothelium-dependent contraction (EDC), -dependent relaxation (EDR) and -independent contraction (EIC) were SP > SPME >> NKA [symbol: see text] NKB [symbol: see text] AANF, SP > SPME > NKA > NKB >> AANF and NKA > AANF > NKB >> SP [symbol: see text] SPME, respectively. SP-induced EDC and EDR were attenuated by an NK1 antagonist but not by an NK2 antagonist. The SP-induced EIC was reduced by an NK2 antagonist. SP-induced EDC was attenuated by aspirin, OKY-046, and S-1452. The EDR was attenuated by L-NAME and methylene blue. The EDC induced by SPME was non-competitively attenuated by CP-99994, an NK1 antagonist. EDR was competitively inhibited by CP-99994. In conclusion, SP and related peptides caused EDC via NK1 receptors and TXA2 production, EDR via NK1 receptors and NO release and EIC via NK2 receptors in rabbit intrapulmonary arteries.
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PMID:[Tachykinin receptor subtypes involved in endothelium-dependent and -independent responses in rabbit intrapulmonary arteries]. 950 16

Using the sucrose-gap technique, we attempted to assess a role for tachykinins (TKs) in mediating noncholinergic excitatory junction potential (EJP) and contraction, in the circular muscle of rat proximal colon. Excitatory responses were evoked by submaximal electrical field stimulation (EFS) in the presence of atropine (1 microM), guanethidine (1 microM), indomethacin (10 microM), and N(omega)-nitro-L-arginine methyl ester (L-NAME) (100 microM). The NK1 receptor antagonist, SR 140,333 (up to 3 microM) or the NK2 receptor antagonists, SR 48,968 and MEN 10,627 (up to 5 microM) produced a partial inhibition of the excitatory responses to EFS. The co-administration of the selective NK1 and NK2 receptor antagonists produced additive effects on the responses to EFS. Selective NK1 receptor agonist, [Sar9, Met (O2)11]-substance P, induced depolarization and contraction, antagonized by SR 140,333, but not by NK2 receptor antagonists. NK2 receptor agonist, [betaAla8]-neurokinin A (4-10), also produced electrical and mechanical excitatory effects that were antagonized by SR 48,968 or MEN 10,627, but not by the NK1 receptor antagonist. Our results provide evidence that, in circular muscle of rat colon, endogenous tachykinins are the main excitatory transmitters for nonadrenergic, noncholinergic (NANC) excitation and their action is mediated by both NK1 and NK2 receptors.
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PMID:Tachykinins mediate noncholinergic excitatory neural responses in the circular muscle of rat proximal colon. 992 7

1. In order to examine the role of nitric oxide (NO) in the tonic neural inhibition in rat proximal colon, the effects of N(omega)-nitro-L-arginine methyl ester (L-NAME) were studied on the spontaneous contractions of circular muscle (monitored as intraluminal pressure changes) and of longitudinal muscle (detected as isometric tension changes). 2. L-NAME (3 x 10(-6)-3 x 10(-4) M) caused a concentration-dependent increase in the amplitude of circular contractions, without affecting those of longitudinal muscle. This effect was prevented by L-arginine (1-5 x 10(-3) M), but not D-arginine. 3. In the presence of tetrodotoxin (10(-6) M), which per se induced increase of the pressure waves, L-NAME (10(-4) M) caused no further effects on the amplitude of the spontaneous contractions. 4. The response to L-NAME (10(-4) M) was unaffected by atropine (10(-6) M), guanethidine (10(-6) M), hexamethonium (up to 3 x 10(-4) M) or alpha-chymotrypsin (up to 5 U ml(-1)). 5. NK2 receptor antagonists, SR 48968 (3 x 10(-6) M) or MEN 10627 (10(-6) M), produced a reduction of the amplitude of the pressure waves but failed to affect the contractile response to L-NAME (10(-4) M). 6. These findings suggest that tonic production of NO from inhibitory neurones influences the degree of contractions of circular muscle. An involvement of an inhibitory peptide as well as disinhibition of cholinergic or NK2-tachykinergic excitatory neurotransmission in the mechanism of NO action can be ruled out.
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PMID:Modulation by nitric oxide of spontaneous mechanical activity in rat proximal colon. 1038 64

This study analyzes both cell migration and exudation responses elicited by substance P (SP) in the mouse pleural cavity. SP caused, 4 h after its administration into the mouse pleural cavity, a dose-related recruitment of leukocytes (ED50 = 14.2 nmol), mainly due to mononuclears. Leukocytes peaked between 2 and 4 h, being followed by a slight decay that remained elevated for up to 24 h. Exudation, although small, was significantly elevated from 2 to 96 h after. NK1 (FK 888) or NK3 (SR 142801), but not NK2 (SR 48968) tachykinin receptor antagonists, significantly inhibited cell migration. HOE 140 and NPC 17731, bradykinin B2 receptor antagonists, caused graded inhibition of cell influx (ID50s of 0.03 and 0.04 pmol), but des-Arg9-Leu8-BK, B1 receptor antagonist, had no effect. The nitric oxide inhibitors L-NOARG and L-NAME, but not D-NAME, significantly inhibited SP-induced pleurisy. Pretreatment of the animals with indomethacin, dexamethasone, terfenadine, theophylline or salbutamol produced significant inhibition of the inflammatory parameters, whereas cromolyn only inhibited exudation. These results indicate that intrapleural injection of SP in mice elicit a long-lasting inflammatory reaction that is characterized by the participation of nitric oxide, kinins, cyclooxygenase metabolites and histamine. Antiasthmatic drugs such as theophylline, salbutamol, dexamethasone, and, to a lesser extent cromolyn, also markedly inhibit this inflammatory reaction. These results provide clear evidence supporting the role played by SP in neurogenic inflammation.
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PMID:Analysis of the inflammatory response induced by substance P in the mouse pleural cavity. 1042 82

The role of endogenous tachykinins and the mechanisms whereby they act on NK2 receptors, modulating spontaneous motility, were investigated in rat isolated proximal colon. The mechanical activity was detected as changes in intraluminal pressure. The NK2 receptor antagonist, MEN 10627, produced a concentration-dependent reduction of the contraction amplitude. [beta-Ala8]-neurokinin A(4-10), an NK2 receptor agonist, and [Sar9, Met(O2)11]-Substance P ([Sar9, Met(O2)11]-SP), an NK1 receptor agonist, induced a concentration-dependent contractile response, characterized by an increase in basal tone with superimposed phasic contractions. MEN 10627 antagonized the response to [beta-Ala8]-neurokinin A(4-10), without affecting that to [Sar9, Met(O2)11]-SP. Tetrodotoxin (TTX), hexamethonium and Nomega-nitro-L-arginine methyl ester (L-NAME) significantly reduced the response to MEN 10627. The NK3 receptor agonist, senktide, was able to activate the nitrergic inhibitory pathway, as it induced a TTX-and L-NAME-sensitive inhibitory effect. [beta-Ala8]-neurokinin A(4-10) was able to antagonize the inhibitory response to senktide. These findings suggest that tachykinins acting on NK2 receptors play a role in the modulation of the spontaneous mechanical activity. The mechanism of this action would be, in part, acting directly on the smooth muscle cells, and, in part neurogenic, sustained by nicotinic inputs, and possibly due to inhibition of NO tonic release.
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PMID:Involvement of tachykinin NK2 receptors in the modulation of spontaneous motility in rat proximal colon. 1101 46

Correolide (1 - 10 microM), a nortriterpene purified from Spachea correae and a selective blocker of Kv1 potassium channels, elicits repetitive twitching in guinea-pig ileum. This effect is not seen in guinea-pig duodenum, portal vein, urinary bladder or uterine strips, nor in rat or mouse ileum. The time course and amplitude of the correolide-induced twitches in guinea-pig ileum are similar to those elicited by electrical stimulation of the enteric nervous system. The correolide-induced twitching is not affected by pre-treatment with capsaicin (1 microM), but is facilitated by the NO synthase inhibitor, N(G)-nitro-L-arginine methyl esther (L-NAME, 200 microM). The correolide-induced twitching is abolished by tetrodotoxin (1 microM) or hexamethonium (100 microM), and is markedly inhibited by nifedipine (0.3 microM) or atropine (0.2 microM). The atropine-resistant component is inhibited by selective antagonists of NK1 and NK2 tachykinin receptors, namely GR 82334 and GR 94800 (1 microM each). The former compound is more effective in inhibiting the correolide-induced, atropine-resistant activity. Correolide intensified the twitching of ileum segments exposed to saturating concentrations of margatoxin (MgTX), which suggests that Kv1 sub-types other than Kv1.1 (Kv1.4 or Kv1.5) are involved in the relatively greater degree of stimulation of the enteric nervous system by correolide, as compared to MgTX. We propose that blockade of Kv1 channels by correolide increases the excitability of intramural nerve plexuses promoting release of acetylcholine and tachykinins from excitatory motor neurons. This, in turn, leads to Ca(2+)-dependent action potentials and twitching of the muscle fibres.
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PMID:Correolide, a nor-triterpenoid blocker of Shaker-type Kv1 channels elicits twitches in guinea-pig ileum by stimulating the enteric nervous system and enhancing neurotransmitter release. 1103 Jul 27


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