Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The desensitization of receptors for substance P in the longitudinal muscle of the guinea-pig ileum has been studied. Receptors for substance P in the muscle became desensitized in the presence of relatively large concentrations of synthetic substance P; a desensitizing concentration of substance P of 7.5 x 10(-9) M shifted the concentration-response curve for substance P about 20-fold to the right, while a desensitizing concentration of 7.5 x 10(-8) M shifted the curve about 300-fold to the right. This desensitization appeared specific; concentration-response curves for carbachol, DMPP, 5-HT and bradykinin were not significantly affected by substance P, 7.5 x 10(-8) M. Furthermore, substance P in concentrations up to 7.5 x 10(-8) M did not modify transmission from either cholinergic nerves or enteric inhibitory nerves when these were stimulated electrically. However, hyoscine-resistant contractions produced by stimulation of nerves in the ileum at 10 Hz were abolished by exposure to concentrations of substance P of 7.5 x 10(-9) M or greater, suggesting that these nerves release a substance similar to or identical with substance P. DMPP evoked small hyoscine-resistant contractions of the ileum. These contractions were also antagonised by desensitization of receptors for substance P. Immunohistochemical studies showed substance P-like immunoreactivity in nerve terminals of both the myenteric and submucous plexuses.
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PMID:Evidence for the release of endogenous substance P from intestinal nerves. 22 22

To investigate the functional relationship between the enteric nervous system and the intestinal neurotensin (N) cells, the release of neurotensin (NT) was measured upon vascular 8-min infusion periods of various neurotransmitters and neuropeptides in an isolated vascularly perfused rat jejunoileum. NT-like immunoreactivity (NT-LI) was measured with an antiserum that specifically recognizes intact NT. The cholinergic agonists methacholine and carbachol produced a strong release of NT-LI (250% and 700% of basal, respectively at 10(-5) M). The infusion of a lower dose (10(-7) M) was less effective in both cases. The nicotinic receptor agonist DMPP (10(-4) M) had no significant effect on NT-LI release. Norepinephrine (10(-6) M) produced a moderate and well-sustained secretion of NT (200% of basal). Infusion of higher doses of these neurotransmitters dramatically increased the arterial pressure. G-amino-n-butyric acid (GABA), histamine, serotonin and dopamine administered at final concentrations up to 10(-5) M had no effect on NT-LI release. In contrast, gastrin-releasing peptide and bombesin induced a dose-dependent transient increase of portal NT-LI (maximal value at 10(-7) M: 1000% of basal) followed by a rapid return to near basal values. Substance P (10(-7) M) evoked a prompt release of NT-LI with a peak at 600% of basal followed by a decline to 200% of basal at the end of the session. Leu-enkephalin and calcitonin-gene-related-peptide (CGRP, 10(-7) M) produced a small rise in portal NT-LI, while Met-enkephalin, dynorphin, vasoactive intestinal peptide (VIP), galanin, neuropeptide Y (NPY), peptide histidine isoleucine (PHI), neuromedin U and thyrotropin releasing hormone (TRH) had no stimulatory effect. Our results indicate that additionally to the secretion of NT induced by cholinergic agents and bombesin, substance P and to a lesser extent Leu-enkephalin are capable of stimulating NT release in the rat.
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PMID:Release of ileal neurotensin in the rat by neurotransmitters and neuropeptides. 167 14

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

Pathways for contractions of in vivo canine small intestine produced by mesenteric nerve stimulation (MNS) were studied. In intact and chronically sympathectomized dogs, contractions of jejunal and ileal segments were largely reduced by intra-arterial infusion of capsaicin (10-100 microM, 0.07 ml/min), substance P (SP) antagonist, (D-Pro4, D-Trp7.9) SP (4-11) (100 microM, 0.14 ml/min), hexamethonium (100-1000 microM, 0.07 ml/min) or atropine (100 microM, 0.07 ml/min). In chronically vagotomized dogs, capsaicin, SP-antagonist or atropine significantly reduced MNS-induced contractions, but hexamethonium did not. In dogs in which the coeliac and superior mesenteric ganglia had previously been removed, MNS caused no response although intra-arterial injection of 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP, 0.1 mumol) caused marked contractions. It may therefore be suggested that extrinsic SP neurons probably originating in spinal ganglia and intrinsic SP neurons receiving input from vagal preganglionic cholinergic neurons are involved in the excitatory pathways to MNS-induced contractions and that activation of these neurons excites myenteric cholinergic neurons, thereby causing contractions of the small intestine.
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PMID:Involvement of substance P neurons in contractions of canine small intestine produced by mesenteric nerve stimulation. 247 34

1. Muscle strips from the dome of the human urinary bladder responded to field stimulation with contractions which were atropine- (3 microM) and tetrodotoxin- (1 microM) sensitive. These contractions were sensitive to omega conotoxin (CTX, 0.1 microM). The atropine- and tetrodotoxin-resistant contractions produced by field stimulation were totally unaffected by CTX. 2. DMPP (30-100 microM), a nicotinic agonist, produced transient bladder contractions which were hexamethonium- and atropine-sensitive. 3. Tachykinins produced a contraction of the human bladder. Among several synthetic tachykinin analogs only those having activity at the NK-2 receptor produced a consistent contractile response. 4. Either capsaicin (1 microM) or calcitonin gene-related peptide (10 nM-0.1 microM) had no motor effect. At 10 microM, capsaicin exerted a depressant effect on nerve-mediated contractions but this effect did not exhibit desensitization. 5. These findings provide evidence that NK-2 receptors are the main if not the sole mediators of the contractile response of the muscle from the dome of the human isolated bladder to tachykinins. 6. No evidence was found for a tachykininergic component in the excitatory response to field stimulation nor for motor responses mediated by capsaicin-sensitive nerves. 7. CTX-sensitive calcium channels are probably present on cholinergic nerve terminals in the human bladder muscle.
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PMID:Further studies on the motor response of the human isolated urinary bladder to tachykinins, capsaicin and electrical field stimulation. 248 3

Several tachykinins (SP, NKA and NPK) are colocalized with CGRP-LI in nerve fibres supplying bronchial smooth muscle, close to and within the lining epithelium, around blood vessels and around local tracheo-bronchial ganglion cells in animals and man. SP-IR and CGRP-IR were also present in the same cells of jugular, nodose and thoracic spinal ganglia but only in nerve fibres in local parasympathetic ganglia and the stellate ganglia, suggesting a sensory origin. After capsaicin treatment there was a selective and nearly total loss of SP- and CGRP-IR nerves in the airways in parallel with a reduction in the corresponding tissue content. Capsaicin-sensitive sensory nerves containing SP-IR in the trachea had a predominant vagal component while in the peripheral airways SP-IR nerves had a dual origin from the vagal nerves and from thoracic spinal ganglia via the stellate ganglia and sympathetic pathways. CGRP-IR, but not SP-LI, was also present in epithelial endocrine cells. A Ca2+-dependent release of tachykinin-LI and CGRP-LI was demonstrated upon perfusion of the guinea-pig lung with K+ as well as capsaicin. Other substances such as bradykinin, histamine and the nicotinic receptor agonist DMPP were also able to induce overflow, suggesting the release of both SP-LI and NKA-LI. The material released upon stimulation with capsaicin was further characterized by HPLC, and the main peak of the immunoreactivity co-eluted with ELE, a smaller peak eluted in the position of NKA, but no clear evidence for the release of material co-eluting with NPK was observed. This suggests that SP and NKA are the main tachykinins released from sensory nerves, while the nature of the ELE-LI remains to be further clarified. Upon i.v. infusion in the guinea-pig in vivo, the disappearance rate of SP-LI and NKA-LI showed half-lives of less than 2 min, while NPK-LI disappeared from the blood in a biphasic manner with two half-lives of 0.9 and 6 min, respectively. NPK given i.v. was converted into NKA-LI. In guinea-pig plasma in vitro, NKA-LI and NPK-LI were stable for 10 min, while SP-LI disappeared rapidly with a half-life of about 10 s. The long half-life of NPK-LI in vivo was also accompanied by a more long-lasting bronchoconstrictor effect of NPK compared to SP. Thus, the differences in pharmacokinetical properties makes it difficult to draw major conclusions about tachykinin receptor subtypes based on biological potencies in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sensory nerves containing tachykinins and CGRP in the lower airways. Functional implications for bronchoconstriction, vasodilatation and protein extravasation. 349 54

We have characterized the contractile responses produced by stimulation of the tachykinin NK2 receptor in the hamster urinary bladder in vitro and in vivo. In isolated bladder strips, neurokinin A (NKA, pD2 7.40, Emax 71% of the response to 80 mM KCl) and the synthetic tachykinin NK2 receptor selective agonist [betaAla8]NKA(4-10) (pD2 7.48, Emax 77% of the response to KCl) both induced a concentration-dependent contraction, whereas the tachykinin NK1 and NK3 receptor selective agonists, [Sar9]substance P sulfone and senktide, respectively, produced a negligible contractile effect. The bicyclic peptide antagonists MEN 11420 and MEN 10627 behaved as competitive antagonists of the response to [betaAla8]NKA(4-10) with apparent pK(B) values of 9.3 and 9.7, respectively. Comparable apparent pK(B) values were estimated against NKA (pK(B) 9.2 and 9.4 for MEN 11420 and MEN 10627, respectively). Under isovolumetric recording of the intravesical pressure, the nicotinic receptor agonist DMPP (0.6 micromol/kg i.v.) produced a phasic contraction of the hamster bladder in vivo that was abolished by hexamethonium (110 micromol/kg i.v.) or by surgical ablation of pelvic ganglia. In vivo [betaAla8]NKA(4-10) (10 nmol/kg i.v.) induced a tonic-type sustained bladder contraction with superimposed high frequency and small amplitude (<12 mmHg) phasic contractions and, in about 70% of cases examined, a few high amplitude (>20 mmHg) phasic contractions. Hexamethonium abolished the high amplitude phasic contractions, indicating their reflex origin. In animals subjected to the ablation of pelvic ganglia, the urinary bladder response to [betaAla8]NKA(4-10) was comparable to that observed after administration of hexamethonium. Moreover, hexamethonium did not affect the contractile responses to [betaAla8]NKA(4-10) in ganglionectomized animals. MEN 10627 and MEN 11420 produced a dose-dependent and long-lasting inhibition of the contractile response to [betaAla8]NKA(4-10): the least effective doses of the two antagonists were 30 and 3 nmol/kg i.v. for MEN 10627 and MEN 11420, respectively. An almost complete and long-lasting inhibition of the response to the agonist was produced at doses of 10 and 100 nmol/kg i.v. of MEN 11420 and MEN 10627. In urethane-anaesthetized hamsters the non-stop intravesical infusion of saline (50 microl/min) produced repetitive micturition cycles which were abolished by hexamethonium (110 micromol/kg i.v.) or by surgical removal of the pelvic ganglia. MEN 11420 (100 nmol/kg) had no significant effect on the volume-evoked micturition reflex in anaesthetized hamsters. In conclusion, the hamster urinary bladder is a suitable preparation for studying the action of tachykinin NK2 receptor antagonists in vivo: in this species, the stimulation of tachykinin NK2 receptors induces bladder contractions. Blockade of tachykinin NK2 receptors does not appreciably modify the volume-evoked micturition reflex in this species.
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PMID:Tachykinin NK2 receptors in the hamster urinary bladder: in vitro and in vivo characterization. 977 15