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)

A long-term culture system of dissociated rat dorsal root (DRG) and trigeminal ganglion cells with high cell density has been developed. Two to 3 weeks after plating, the cultures consist of a nearly pure population of sensory neurons, which can be kept for more than 2 months in culture. Cultured neurons synthesize and release the tachykinins substance P (SP) and substance K (SK, neurokinin A) with a time course similar to that observed in vivo. High-pressure liquid chromatography (HPLC) analysis of peptides extracted from neuronal cultures and synthetic tachykinins revealed identical retention characteristics. Northern blot analysis of mRNAs from cultured cells with a specific tachykinin-probe demonstrated that the preprotachykinin-gene is expressed in preparations of both DRG and trigeminal ganglia cells. Depolarizing stimuli such as high potassium (47 mM) evoked a peptide release from cultured neurons in a strictly Ca(++)-dependent manner. Capsaicin, a compound known to stimulate nociceptive sensory neurons, dose-dependently released tachykinins in concentrations as low as 10(-9) M. Only total absence of Ca++ ions from the incubation medium abolished the capsaicin-induced peptide release. Nifedipine, a blocker of voltage-dependent L-type Ca++ channels, completely blocked the potassium-induced release of SP but did not reduce the capsaicin-evoked release. Mediator substances of pain and inflammation, such as bradykinin, serotonin, and histamine, triggered the release of tachykinins from sensory neurons in vitro. These results clearly demonstrate that the neurons characterized express properties similar to those of sensory neurons in vivo and provide model systems for detailed studies of the biosynthesis and release of neuropeptides as well as the participation of sensory neurons in pain and inflammatory reactions.
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PMID:Biosynthesis and release of tachykinins from rat sensory neurons in culture. 179 53

The effects of chronic acrylamide treatment on the autonomic nervous system were investigated by histochemical and pharmacological studies. Histochemical studies showed that acrylamide caused different degrees of damage to different nerve fibre types: calcitonin gene-related peptide (CGRP)-immunoreactive (IR) nerves showed the greatest reduction in intensity and number; noradrenaline (NA)-containing nerves were somewhat less affected; substance P (SP)-IR nerves were reduced in number, but this was not significant. The profiles of SP- and particularly of CGRP-IR nerves from treated animals were noticeably different to those from the control group, being flattened and irregular. Periarterial nerve stimulation (4-32 Hz) of the isolated rat mesenteric arterial bed preparation at basal tone elicited frequency-dependent vasoconstrictor responses. The magnitude of these responses was significantly reduced at higher frequencies in acrylamide-treated animals. In preparations with tone raised by the addition of methoxamine (10(-5) M), and in the presence of guanethidine (5 x 10(-6) M), periarterial nerve stimulation elicited vasodilator responses. These responses, which result from stimulation of sensory nerves, were greatly reduced in acrylamide-treated animals. There was a tendency for mesenteric beds from acrylamide-treated animals to show increased vasoconstrictor responses to doses of exogenous NA, although this was not significant. Responses to exogenous adenosine 5'-triphosphate (a cotransmitter with NA from sympathetic nerves) were not affected. In the raised-tone preparation, vasodilator responses to exogenous CGRP (the principal vasodilator sensory transmitter of rat mesenteric arteries) were not affected by acrylamide treatment. Hence, it is unlikely that the reduced responses to nerve stimulation were due to defects in the postjunctional receptors for the principal transmitters of sympathetic and sensory-motor nerves. There was no difference in the ability of mesenteric beds from control and treated animals to vasodilate in response to acetylcholine or sodium nitroprusside, or to vasoconstrict in response to potassium chloride, indicating normal smooth muscle and endothelial responses. These results suggest that chronic acrylamide treatment produces peripheral autonomic neuropathy of rat mesenteric vessels, manifested as a dysfunction of sympathetic and sensory-motor nerves. Furthermore, the graded destruction of nerve types, such that damage occurred in the order: CGRP-IR greater than NA greater than SP-IR, indicated a differential sensitivity of different nerves to this toxin.
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PMID:Acrylamide-induced autonomic neuropathy of rat mesenteric vessels: histological and pharmacological studies. 194 19

The effect of a potassium channel activator, cromakalim (BRL 34915), on excitatory nonadrenergic noncholinergic (e-NANC) and cholinergic neural bronchoconstriction was studied in guinea pigs. We monitored airway opening pressure as an index of airway caliber. After atropine (1 mg/kg iv.) and propranolol (1 mg/kg iv.), bilateral vagal stimulation evoked an e-NANC response. Cromakalim did not alter basal airway caliber, but reduced the e-NANC response to vagal stimulation in a dose-dependent manner, with a maximal inhibition of 71.9 +/- 9.2% (mean +/- S.E.) at 400 micrograms/kg i.v. (P less than .01). Pretreatment with phentolamine (2.5 mg/kg i.v.) had no effect on the inhibitory response produced by cromakalim but glibenclamide (25 mg/kg iv.), an inhibitor of ATP-sensitive potassium channels, blocked its effect. Cromakalim had no inhibitory effect on exogenous substance P (5-25 micrograms/kg i.v.)-induced bronchoconstriction. In animals depleted of tachykinins by capsaicin (50 mg/kg s.c.) pretreatment, cromakalim had an inhibitory effect on both vagalcholinergic and exogenous acetylcholine (0.3-2 micrograms/kg i.v.)-induced bronchoconstriction, although the inhibitory effect was significantly greater on neural stimulation. We conclude that potassium channels modulate both e-NANC and cholinergic neurotransmission, and to a lesser extent acetylcholine-induced bronchoconstriction in guinea pig airways.
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PMID:A potassium channel activator modulates both excitatory noncholinergic and cholinergic neurotransmission in guinea pig airways. 210 38

Potassium (K+) channels are present on airway smooth muscle cells, and their activation results in hyperpolarization and relaxation. Because these effects may have therapeutic relevance to asthma, we examined the activity of the active L-enantiomer of cromakalim, BRL 38227 (lemakalim), a selective K+ channel activator, against a variety of spasmogens in human bronchi in vitro. BRL 38227 produced relaxation of bronchi with either resting tone or tone induced by histamine, carbachol, neurokinin A, or KCl (20 mM) with an efficacy (%Emax) of 60 to 80% of that of isoproterenol and an EC50 (the concentration producing 50% of the maximal response) of 0.2 to 0.6 microM. However, BRL 38227 had a significantly lower potency and efficacy against 80 mM KCl than against the other spasmogens (%Emax, 12% of isoproterenol and EC50, 7.2 microM; p less than 0.005 and p less than 0.001, respectively), supporting the view that BRL 38227 acts on K+ channels. The D-enantiomer BRL 38226 was less potent (EC50, 2.6 microM) than BRL 38227 and produced only 43% of the isoproterenol relaxation. BRL 38227-induced relaxation was significantly inhibited by the ATP-sensitive K+ channel antagonist glibenclamide (0.1 and 1 microM), with a three-fold and eight-fold shift to the right of the dose-response curve, respectively. In the presence of a maximal relaxation induced by the calcium voltage-dependent channel antagonist verapamil, BRL 38227 was able to produce an additional 37% relaxation response. Thus, BRL 38227 is an effective relaxant of human airway smooth muscle, and this activity results from an action at K+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The action of a potassium channel activator, BRL 38227 (lemakalim), on human airway smooth muscle. 212 15

The aim of this study was to assess whether omega conotoxin fraction GVIA, a potent blocker of N- and L-type voltage-sensitive calcium channels, might interfere with reflex responses (micturition, blood pressure rise in spinal rats) produced by activation of capsaicin-sensitive sensory nerves of the rat urinary bladder. The effect of conotoxin was also investigated on reflex micturition persisting after capsaicin pretreatment. Following topical application onto the bladder, conotoxin did not affect the volume threshold to elicit micturition although it reduced the amplitude of volume-evoked bladder contractions. Likewise, topical conotoxin did not prevent the reflex rise in blood pressure elicited by sudden bladder distension or topical application of capsaicin onto the bladder. In contrast, topical lidocaine strongly prevented both reflex responses. After intrathecal administration, conotoxin produced a dose-dependent inhibition of volume-evoked bladder contractions and the cardiovascular reflex produced by mechanical or chemical stimulation of bladder nerves. Intrathecal conotoxin inhibited micturition also in rats pretreated with capsaicin (50 mg/kg s.c., 4 days before). Depolarization by high potassium (80 mM) produced release of both substance P- and calcitonin gene-related peptide-like immunoreactivity from superfused slices of the dorsal half of rat spinal cord. Capsaicin (1 microM) produced a similar effect, and a previous exposure to capsaicin prevented the effect of potassium. Conotoxin (0.1 microM) significantly reduced (about 50%) the potassium-induced release of neuropeptides from the dorsal half of the rat spinal cord. These findings indicate that conotoxin-sensitive calcium channels in the rat spinal cord play a role in the neurotransmission along reflex pathways activated by stimulation of capsaicin-sensitive nerves in the urinary bladder.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of omega conotoxin on reflex responses mediated by activation of capsaicin-sensitive nerves of the rat urinary bladder and peptide release from the rat spinal cord. 232 50

Intracellular recordings were made from neurones in the myenteric plexus of the guinea-pig ileum. Presynaptic nerves were excited by a focal stimulating electrode on an interganglionic strand. Fast excitatory postsynaptic potentials (e.p.s.ps) were depressed in amplitude by morphine and [Met5]enkephalin in the concentration range of 1 nM-1 microM. Nicotinic depolarizations evoked by exogenously applied acetylcholine (ACh) were not affected by these opioids. Hyperpolarization of the presynaptic fibres probably contributed to the depression of the fast e.p.s.p. because fast e.p.s.ps evoked by low stimulus voltages were more depressed than those evoked by high stimulus voltages and fast e.p.s.ps resulting from activation of a single presynaptic fibre were blocked in a non-graded manner. Opioids depressed the slow e.p.s.p. in those neurones in which they did not change the resting membrane potential. The slow e.p.s.p. was increased in amplitude in those neurones hyperpolarized by opioids. Depolarizations resulting from application of barium, substance P or ACh were also enhanced by opioids. Equivalent circuit models in which opioids increase, and substance P or ACh decrease, the same potassium conductance could account for this enhancement. The actions of opioids were prevented or reversed by naloxone (1 nM-1 microM). It is concluded that morphine and enkephalin inhibit the release of ACh and a non-cholinergic transmitter from fibres of the myenteric plexus, and that this may involve a hyperpolarization of presynaptic fibres. Additionally, opioids can interact postsynaptically with other substances which affect membrane potassium conductances.
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PMID:Opioid inhibition of synaptic transmission in the guinea-pig myenteric plexus. 241 22

The large B cells of bull-frog sympathetic ganglia are well known to be depolarized by slow synaptic transmission, muscarinic agonists, analogues of luteinizing hormone-releasing hormone (LHRH), and substance P. Voltage-clamp analysis shows that these actions result from two underlying mechanisms: inhibition of the M-current, a voltage-dependent potassium current; and in some cells, an inward current associated with an increase in conductance. The additional inward current appears as a voltage-insensitive change in the instantaneous conductance (i.e. apparent leak conductance). The additional inward current is typically slower in onset and offset than is M-current inhibition. It is typically seen for higher concentrations and longer durations of agonist application. In many cells, only a decrease in M-current can be demonstrated. Muscarine inhibits the M-current with 50% inhibition (I50) at 0.7 microM. At least 86% of the M-current is muscarine sensitive. At comparable concentrations, oxotremorine produces less M-current inhibition than does muscarine. Some analogues of teleost LHRH (T-LHRH) are more potent as M-current inhibitors than T-LHRH itself. Those peptides tend to act more slowly than T-LHRH. Substance P shows variable potency for M-current inhibition, with I50 s ranging from 2 nM to greater than 2 microM on different cells. The response to long applications of substance P desensitizes in some cells, which has not been observed for comparable applications of muscarinic or LHRH agonists. Other tachykinins (including substance K) inhibit the M-current. C-terminal fragments of substance P are ineffective, and M-current inhibition by substance P is not blocked by [D-Pro2,D-Trp7,9]- or [D-Arg1,D-Pro2, D-Trp7,9,Leu11] substance P. The slow muscarinic excitatory post-synaptic potential (e.p.s.p.) produces a graded inhibition of up to 90% of the M-current. Occasional cells show an additional inward current with an associated increase in conductance during the slow e.p.s.p. This effect is less marked than with exogenous muscarinic agonists. The late, slow e.p.s.p., which is produced by stimulation of high threshold C-fibre inputs and is resistant to cholinergic antagonists, also involves M-current inhibition. An additional inward current can be observed in some cells. M-current inhibition (by agonists or slow synaptic potentials) increases the number of spikes produced by a given depolarizing current, often allowing maintained firing. This action is not mimicked by equivalent depolarization, and is still seen when the cell is manually clamped to the original resting potential.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Muscarinic and peptidergic excitation of bull-frog sympathetic neurones. 241 36

Mechanisms regulating peptidergic, noradrenergic and cholinergic development were compared in dissociated cell cultures of neonatal rat sympathetic ganglia. The majority of cultured neurons contained at least two neurotransmitters and many neurons contained three or more. These studies were undertaken to determine whether co-existing transmitters were co-ordinately regulated by the environment. Co-culture of sympathetic neurons with ganglion non-neuronal cells increased substance P and choline acetyltransferase activity but decreased somatostatin and tyrosine hydroxylase activity. Conversely, elimination of non-neuronal cells virtually abolished neuronal expression of substance P and choline acetyltransferase and increased somatostatin and tyrosine hydroxylase. Consequently, under these conditions, somatostatin and tyrosine hydroxylase were similarly regulated, whereas substance P was associated with choline acetyltransferase. By contrast, stimulation of adenylate cyclase or treatment with membrane-permeable adenosine 3',5'-phosphate analogs increased tyrosine hydroxylase and decreased choline acetyltransferase, but had no effect on substance P or somatostatin levels. Moreover, potassium- or veratridine-induced membrane depolarization increased tyrosine hydroxylase but decreased substance P, somatostatin and norepinephrine levels. However, inhibition of neurotransmitter release with magnesium or calcium-free medium prevented the decrease in norepinephrine levels but not the decrease in substance P and somatostatin. Consequently, the effects of membrane depolarization on peptide levels cannot be ascribed to release and subsequent depletion of substance P and somatostatin and must result from decreased net synthesis (synthesis minus catabolism) of the transmitters. Nerve growth-factor treatment also differentially regulated transmitter metabolism; nerve growth factor increased protein-specific activities of tyrosine hydroxylase and choline acetyltransferase but did not increase the protein-specific content of substance P and somatostatin. Quantitative transmitter expression was also influenced by neuron density; increasing density elevated substance P and choline acetyltransferase activity but decreased somatostatin and tyrosine hydroxylase activity per neuron. Finally, culture of sympathetic neurons in a defined (serum-free) medium also altered some but not all traits, decreasing substance P, somatostatin and choline acetyltransferase without any change in tyrosine hydroxylase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential regulation of peptide and catecholamine characters in cultured sympathetic neurons. 241 73

The development of substance P, somatostatin, and choline acetyltransferase activity was examined in embryonic rat striatum in vivo and in culture. The study was undertaken to help define mechanisms by which diverse neurotransmitter phenotypes may be regulated within the same structure in the brain. Choline acetyltransferase (CAT) was present in striatum before gestational Day 13.5 (E13.5), and enzyme levels increased continually between E13.5 and birth. By contrast, substance P (SP) and somatostatin (SS) did not develop in vivo until E15, and peptide levels fluctuated between E15 and birth, indicating that striatal peptidergic and cholinergic development were regulated differently. To define mechanisms mediating the differential regulation of striatal peptidergic and cholinergic neurons, neurotransmitter development was examined in embryonic striatum in vitro. Cultured striatal neurons from E13.5 embryos expressed substance P and somatostatin de novo after several days in culture, and peptide levels and CAT activity increased significantly in vitro. Each transmitter phenotype was regulated in vitro by a different constellation of environmental factors, and many factors differentially influenced SP, SS, and CAT development. For example, coculture of striatum with a target tissue, the ventral mesencephalon (substantia nigra), increased CAT activity and SP levels but had no significant effect on levels of SS. Moreover, there were widely differing effects on CAT, SP, and SS development of medium conditioned by exposure to a variety of cell types, indicating that the three transmitter systems were regulated by different soluble factors. Potassium-induced membrane depolarization also exerted different effects on the different transmitter traits, elevating CAT activity but decreasing SP and SS. Finally, insulin was required for the survival of SP-containing neurons, but not for the survival of SS- or CAT-containing neurons, indicating that the survival of different populations of striatal neurons was dependent upon different factors. Our observations suggest that different populations of neurons in the striatum are regulated by different mechanisms, so that alterations in the environment may produce strikingly diverse responses in the development of different phenotypic traits within the same structure.
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PMID:Differential regulation of cholinergic and peptidergic development in the rat striatum in culture. 241 2

This study was initiated to evaluate the effect of luminally administered serotonin (5-hydroxytryptamine) and substance P on jejunal handling of water and electrolytes. Five dogs with chronic cannulated jejunal Thiry-Vella loops were studied. The isolated jejunal segments were perfused at 2 ml/min for 2 hours with an isosmotic, isothermic perfusate containing labeled polyethylene glycol for recovery calculation. Fluxes of water and sodium, chloride, and potassium were calculated during 30 minute baseline, 60 minute study, and 30 minute recovery periods. Substance P was administered intraluminally at 25 pg/ml, whereas serotonin was perfused at 600 ng/ml. Neither hormone was absorbed into the portal circulation. Intraluminal serotonin converted absorption to secretion of water from 43 +/- 23 to -105 +/- 25 microliters/min, sodium from 7.3 +/- 3.1 to -15.7 +/- 4.1 microEq/min, chloride from 4.4 +/- 3.4 to -16.4 +/- 3 microEq/min, and potassium from 0.16 +/- 0.20 to -0.86 +/- 0.17 microEq/min. Secretion ceased on cessation of serotonin perfusion. Substance P perfusion induced secretion of chloride (3.6 +/- 1.9 to -9.2 +/- 2.9 microEq/min) but only significantly decreased absorption of water (73 +/- 13 to 13 +/- 21 microliters/min) and sodium (8.1 +/- 1.9 to 0.2 +/- 3.1 microEq/min); in contrast, there was no significant change in jejunal handling of potassium.
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PMID:Effect of luminally administered serotonin and substance P on jejunal handling of water and electrolytes. 241 2


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