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 characteristics of Ca2+ entry activated by surface receptor agonists and membrane depolarization were studied in the rat pancreatoma cell line, AR4-2J. Ca2+ mobilization activated by substance P, bombesin, or muscarinic receptor stimulation was found to involve both Ca2+ release and entry. In addition, depolarization of the surface membrane of AR4-2J cells with elevated concentrations of K+ activated Ca2+ entry. Ca2+ entry induced by membrane depolarization was inhibited by the L-channel antagonist, nimodipine, while that due to surface receptor agonists was not inhibited by this agent. The microsomal Ca(2+)-ATPase inhibitor, thapsigargin, caused both depletion of the agonist-sensitive intracellular Ca2+ pool and sustained Ca2+ influx indistinguishable from that produced by bombesin or methacholine. These results confirm that, unlike the pancreatic acinar cells from which they are presumably derived, AR4-2J cells express voltage-sensitive, dihydropyridine-inhibitable Ca2+ channels. However, in contrast to previous reports with this cell line, in the AR4-2J cells in use in our laboratory, and under our experimental conditions, surface receptor agonists (including substance P) do not cause Ca2+ influx through voltage-sensitive Ca2+ channels. Instead, we conclude that agonist-activated Ca2+ mobilization is initiated by (1,4,5)IP3-mediated intracellular Ca2+ release and that Ca2+ influx is regulated primarily, if not exclusively, by the state of depletion of the (1,4,5)IP3-sensitive intracellular Ca2+ pool.
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PMID:Mechanisms of activated Ca2+ entry in the rat pancreatoma cell line, AR4-2J. 137 21

We examined the direct effect of motilin on longitudinal and circular smooth muscle cells isolated from the guinea pig small intestine. In addition, the effects of 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxy-benzoate hydrochloride (TMB-8, an inhibitor of intracellular Ca(2+)-release), verapamil (a voltage-dependent Ca(2+)-channel blocker), and removal of extracellular Ca2+ were investigated to evaluate the role of intracellular Ca2+ stores and extracellular Ca2+ on the muscle contraction induced by motilin. The effects of atropine (a muscarinic receptor antagonist), spantide (a substance P receptor antagonist) and loxiglumide (a CCK-receptor antagonist) were also examined to determine whether the motilin-induced contraction was independent of those receptors. Motilin induced a contraction of the longitudinal and circular smooth muscle cells in a dose-dependent manner with the maximal effect attained after 30 seconds of incubation. The ED50 values were 0.3 nM and 0.05 nM, respectively. TMB-8 suppressed completely the motilin-induced contraction of both types of smooth muscle cells. Verapamil had only a slight suppressive effect. Removal of extracellular Ca2+ did not have any significant influence on motilin-induced contraction. The contractile response to motilin was not affected by atropine, spantide or loxiglumide. Our findings showed that:1) motilin has a direct contractile effect on both longitudinal and circular smooth muscle cells; 2) this contractile effect is not evoked via muscarinic, substance P or CCK receptors, and 3) the intracellular release of Ca2+ plays an important role in the contractile response to motilin on both types of smooth muscle cells.
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PMID:Direct contractile effect of motilin on isolated smooth muscle cells of guinea pig small intestine. 138 65

Neurons expressing the m1, m2, and m4 muscarinic receptor genes in the adult rat striatum were identified and characterized by using several in situ hybridization and immunohistochemical procedures. Combined in situ hybridization for the simultaneous detection of two mRNAs in the same section or in adjacent sections as well as in situ hybridization and immunohistochemistry on adjacent sections permitted us to identify the neurons containing m1, m2, or m4 receptor mRNA. Our observations demonstrate that m1, m2, and m4 receptor genes are expressed in one or several phenotypically distinct neuronal populations. The m1 receptor gene was the most widely expressed (85% of the striatal neurons). Most cholinergic neurons (80% or more) contain m1, m2, and m4 receptor mRNAs. Almost all the substance P neurons contain m1 and m4 receptor mRNA. All enkephalinergic neurons contained m1 receptor mRNA, but only 39% contained m4 receptor mRNA. Most somatostatin and neurotensin neurons expressed the m1 receptor gene, but only a few (15% and 9%, respectively) contained m4 receptor mRNA. The present study offers anatomical evidence that ACh may act directly in complex ways on the main neuronal populations of the striatum through muscarinic receptors. The m1, m2, and m4 receptors may act as autoreceptors to control ACh release and possibly other parameters of ACh neurons. On the other hand, the m1 and m4 receptors may act as heteroreceptors in cholinoceptive efferent neurons (enkephalin and substance P neurons) and other neurons (somatostatin/neuropeptide Y and neurotensin neurons). The presence of m4 receptor mRNA in only parts of the enkephalin, somatostatin, and neurotensin neuronal populations indicates that muscarinic receptor gene expression contributes to the functional and anatomical heterogeneity of the striatum that may relate to higher order of organization, including patch-matrix compartmentalization. The wide expression of m1 and m4 receptor genes in the striatum suggests that ACh may directly influence neurotransmitter release and synthesis in striatal efferent and intrinsic neurons. Our results imply that the specific pattern of expression of the muscarinic receptor genes mediates direct effects of ACh on activities and functions of chemically and topologically defined striatal neuronal populations. Since the expression of muscarinic receptors occurred in the three main neuronal populations of the striatum, namely ACh, enkephalins, and substance P neurons that also express dopamine receptors, it is highly probable that ACh and dopamine may act together at the single-cell level to influence striatal functions.
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PMID:Phenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes. 152 98

The effects of capsaicin on urinary bladder function have been investigated in adult rats. Ten days after capsaicin treatment immunocytochemical investigations showed a nearly complete disappearance of substance P (SP) and calcitonin gene-related peptide (CGRP) in all parts of the bladder. Recordings of micturition patterns and cytometrical investigations in conscious animals revealed no functional effects of capsaicin treatment. In-vitro experiments showed that the contractile response to substance P was similar before and after capsaicin treatment and CGRP exerted no contractile effects on the urinary bladder in either group of rats. The concentration-response curve to carbachol as well as the frequency-response curve to electrical stimulation were significantly shifted to the left in bladder muscle after capsaicin treatment. However, the maximal responses were similar in control and capsaicin-treated bladders. In the presence of scopolamine the maximal response to electrical stimulation was clearly lower in bladders subjected to capsaicin treatment than in controls. In conclusion, depletion of substance P and CGRP in the rat urinary bladder by capsaicin induced no supersensitivity to these peptides. However, the increased sensitivity to carbachol and to electrical stimulation seen after capsaicin treatment indicates the development of a supersensitivity to muscarinic receptor stimulation. Despite this supersensitivity in vitro no functional effects of capsaicin treatment were found in vivo.
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PMID:Muscarinic supersensitivity in the rat urinary bladder after capsaicin pretreatment. 169 75

The role of submucosal neurons in anaphylactic-like responses in colonic epithelium from immunized guinea pigs was examined 6-8 wk after inoculation with 2 x 10(3) infective Trichinella spiralis larvae. Serosal addition of T. spiralis antigen (20 micrograms/ml) to muscle-stripped segments of colon set up in flux chambers evoked a maximum increase in short-circuit current within 5 min in immune, but not nonimmune, guinea pigs. Quercetin, a membrane-stabilizing drug, and pyrilamine, a histamine H1 receptor antagonist, attenuated epithelial responses evoked by T. spiralis antigen. Antigen-induced epithelial responses were reduced by neural blockade with tetrodotoxin and by the muscarinic receptor antagonist atropine but not by blockade of nicotinic receptors with mecamylamine. Antigenic challenge of colonic mucosa from immune guinea pigs enhanced the secretory responses to endogenously released neurotransmitters evoked by electrical field stimulation and substance P. In the presence of antigen, the tetrodotoxin-insensitive component of the carbachol response was enhanced and was reversed by quercetin but not pyrilamine. The results suggest that submucosal cholinergic nerves play a role in mediating the rapid epithelial responses evoked by worm antigen in the colonic mucosa of T. spiralis-immune guinea pigs. Interaction of immunological mediators with neurotransmitters in the submucosal plexus augments the secretory mucosal response triggered by T. spiralis in immunized hosts.
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PMID:Neuroimmune regulation of colonic secretion in guinea pigs. 170 1

Outside diameter of isolated submucosal arterioles in guinea pig colon were monitored to examine vasodilator innervation to these gastrointestinal microvessels. Electrical stimulation of intrinsic submucosal ganglia dilated submucosal arterioles that had been preconstricted with vasopressin or norepinephrine. In approximately 50% of arterioles examined, the muscarinic receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 10 nM) abolished nerve-evoked vasodilations; 4-DAMP (500 nM) only partially inhibited the response in the other 50%. No significant differences in the nerve-evoked vasodilations were observed after extrinsic denervation of sympathetic and sensory fibers and removal of myenteric neurons by surgical myectomy. Immunohistochemistry demonstrated both substance P (SP) and vasoactive intestinal polypeptide (VIP) fiber projections to arterioles after sensory denervation and myectomy. Superfusion with muscarine and SP, but not with VIP or calcitonin gene-related peptide (CGRP), also dilated the arterioles; concentrations of muscarine and SP producing half-maximal responses were 35 and 6 nM, respectively. However, local pressure ejection of both CGRP and VIP dilated the arterioles. The SP receptor antagonist [D-Arg1,D-Phe5,D-Trp7,9,Leu11]SP reduced vasodilations in response to ganglionic stimulation as well as to pressure ejection of both SP and VIP. This study demonstrates that submucosal arterioles in the guinea pig distal colon receive a cholinergic as well as a noncholinergic vasodilator input from neurons in the submucosal plexus. SP and VIP are both likely candidates as the noncholinergic vasodilator transmitter to colonic gastrointestinal microvessels.
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PMID:Cholinergic and noncholinergic submucosal neurons dilate arterioles in guinea pig colon. 171 16

Electrical stimulation of the right vagus nerve causes a biphasic contraction of the guinea pig isolated right bronchus. The "first-phase" is blocked by hexamethonium or atropine and the "second-phase" is eliminated by capsaicin pretreatment. We investigated a potential interaction between capsaicin-sensitive nerves and cholinergic nerves in the guinea pig bronchus. Hexamethonium (100 microM) abolished the first-phase contraction but had no effect on the capsaicin-sensitive second-phase contraction. In the presence of hexamethonium, atropine (0.1 microM) significantly decreased the amplitude of the second-phase contraction by 28%. Similar results were observed with the M3-selective muscarinic receptor antagonist, 4-diphenyl-acetoxy-M-methylpipe-radine, but not with the M2 muscarinic antagonist, AFDX-116. Atropine also reduced contractions induced by exogenously applied neurokinin A. We then analyzed the effect of stimulating capsaicin-sensitive fibers with electrical field stimulation on vagus nerve evoked cholinergic contractions. By reducing the stimulus intensity we were able to evoke vagus nerve-mediated contractions that were exclusively cholinergic in nature. The cholinergic contractions were significantly increased after stimulation of capsaicin-sensitive fibers by about 50%. By contrast, contractions elicited by exogenous methacholine were unaffected after field stimulation of capsaicin-sensitive responses. Our findings indicate that the contractions of the guinea pig bronchus elicited by stimulation of capsaicin-sensitive nerves are due in part to muscarinic cholinergic receptor activation. Secondly, our data demonstrate that the cholinergic contractions elicited by vagal preganglionic nerve stimulation are potentiated by neurotransmitter(s) released from capsaicin-sensitive fibers in bronchus.
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PMID:Functional interactions between capsaicin-sensitive and cholinergic nerves in the guinea pig bronchus. 171 77

Intracellular recording methods were used to investigate the actions of the putative M1 muscarinic receptor antagonist telenzepine on the electrical and synaptic behavior of myenteric neurons. Telenzepine had no effect on resting membrane potential, input resistance, excitability and antidromic potentials in both AH/type 2 and S/type 1 neurons, when applied in concentrations of 0.1-2000 nM, although higher concentrations (10-100 microM) did have a significant non-specific effect on the postsynaptic membrane. Micromolar concentrations of telenpzepine (1-2 microM) had no effect on excitatory responses to substance P, vasoactive intestinal peptide, the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium or the nicotinic action of acetylcholine. Nicotinic fast excitatory postsynaptic potentials were also unaffected by 2 microM telenzepine. In contrast, at submicromolar concentrations (100 nM), telenzepine abolished responses to either muscarine or the muscarinic component of the acetylcholine response. The excitatory effect of muscarine at postsynaptic M1 receptors was dose dependently inhibited by telenzepine (0.1-1000 nM) at concentrations which had no effect on the electrical properties of the cells. This effect was slowly reversible, usually requiring more than 60 min for significant recovery. The threshold dose of telenzepine as an antagonist of the muscarinic depolarization in AH/type 2 neurons was in the range of 0.1-1 nM. The IC50 concentration of telenzepine needed to abolish the response was 8.5 nM. A small proportion of stimulus-evoked slow excitatory postsynaptic potentials in both AH/type 2 and S/type 1 cells were abolished by 1 microM telenzepine, while the majority of them remained unaffected, indicating that some slow excitatory postsynaptic potentials are mediated by the muscarinic action of released acetylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neuropharmacology of the muscarinic antagonist telenzepine in myenteric ganglia of the guinea-pig small intestine. 186 79

Guanine nucleotide binding proteins (G proteins) sensitive to pertussis toxin (PTX) mediate the muscarinic receptor responses in several tissues. Therefore, the present study sought to investigate whether smooth muscle contractions and/or endothelium-dependent relaxations in response to acetylcholine (ACh) and other agonists were sensitive to PTX. In endothelium-denuded rabbit pulmonary artery rings, ACh, clonidine and serotonin produced concentration-dependent contractions which were markedly inhibited in nominally Ca+(+)-free medium and abolished in the presence of ethylene glycol bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (0.2 mM). In endothelium-denuded arterial rings obtained from rabbits treated in vivo with PTX (5 micrograms/kg i.v., 5 days before sacrifice) maximum contractions to ACh, clonidine and serotonin were inhibited by 77, 67 and 35%, respectively. Contractions induced with KCl (10-40 mM) were also abolished in Ca+(+)-free medium, but they were not affected by PTX. Endothelium-dependent relaxations of phenylephrine-contracted pulmonary arteries in response to ACh adenosine triphosphate and substance P were also reduced or abolished upon removal of extracellular Ca++. However, the endothelium-dependent relaxations were not affected by PTX. These data demonstrate that contractions of pulmonary arterial smooth muscle cells after stimulation through muscarinic receptors, alpha adrenoceptors and serotonin receptors require the influx of extracellular Ca++. This receptor-stimulated Ca++ influx is likely to be regulated by a PTX-sensitive G protein. Also, the induction of release of relaxing factor from endothelial cells of the pulmonary artery via muscarinic, purinergic or substance P receptors requires extracellular Ca++. However, in these cells, a different mode of signal transduction, insensitive to PTX, seems to be involved.
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PMID:Pertussis toxin inhibits contractions but not endothelium-dependent relaxations of rabbit pulmonary artery in response to acetylcholine and other agonists. 215 2

Rats were subjected to infravesical outflow obstruction for six weeks. The bladder function was followed by cytometrical and in vitro investigations and by recordings of micturition pattern before and after removal of the obstruction. Cytometrical investigations showed that outflow obstruction for six weeks induced a bladder instability. Further, in the presence of obstruction the micturition pressure was large as was the bladder capacity and the rats had residual urine. After removal of the obstruction the bladder function rapidly normalized. The bladder instability disappeared within one week, bladder capacity decreased as did the micturition pressure. Moreover, only a minor amount of residual urine was present post-obstruction. In vitro investigation showed that the response to carbachol and to electrical stimulation was similar in normal and obstructed bladders. However, after removal of the obstruction a supersensitivity to carbachol as well as to electrical stimulation had developed. Obstructed bladders showed a markedly decreased response to substance P. The sensitivity to substance P was rapidly enhanced post-obstruction and after four days the response was restored to the control level. The present study shows that the bladder function in rats with infravesical outflow obstruction rapidly normalized after removal of the obstruction. The disappearance of the bladder instability despite the developed supersensitivity to muscarinic receptor stimulation supports the opinion that the bladder instability is not of muscarinic origin.
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PMID:On the reversibility of functional bladder changes induced by infravesical outflow obstruction in the rat. 232 92


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