Substance P-induced skin inflammation is not modulated by a single dose of sitagliptin in human volunteers

2011 ◽  
Vol 392 (3) ◽  
Author(s):  
Eric Grouzmann ◽  
Paul Bigliardi ◽  
Monique Appenzeller ◽  
André Pannatier ◽  
Thierry Buclin
Keyword(s):  
Substance P ◽  
Skin Inflammation ◽  
Neutral Endopeptidase ◽  
Intradermal Injection ◽  
Sensory Nerves ◽  
Double Blind Study ◽  
Pain Sensation ◽  
Double Blind ◽  
Burning Pain ◽  
Neurokinin 1

Abstract Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.

Interleukin-1β-induced airway hyperresponsiveness enhances substance P in intrinsic neurons of ferret airway

2002 ◽  
Vol 283 (5) ◽  
pp. L909-L917 ◽  
Author(s):  
Z.-X. Wu ◽  
B. E. Satterfield ◽  
J. S. Fedan ◽  
R. D. Dey
Keyword(s):  
Smooth Muscle ◽  
Substance P ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Sensory Nerves ◽  
Tracheal Smooth Muscle ◽  
Fiber Density ◽  
Smooth Muscle Contractility ◽  
Neurokinin 1

Interleukin (IL)-1β causes airway inflammation, enhances airway smooth muscle responsiveness, and alters neurotransmitter expression in sensory, sympathetic, and myenteric neurons. This study examines the role of intrinsic airway neurons in airway hyperresponsiveness (AHR) induced by IL-1β. Ferrets were instilled intratracheally with IL-1β (0.3 μg/0.3 ml) or saline (0.3 ml) once daily for 5 days. Tracheal smooth muscle contractility in vitro and substance P (SP) expression in tracheal neurons were assessed. Tracheal smooth muscle reactivity to acetylcholine (ACh) and methacholine (MCh) and smooth muscle contractions to electric field stimulation (EFS) both increased after IL-1β. The IL-1β-induced AHR was maintained in tracheal segments cultured for 24 h, a procedure that depletes SP from sensory nerves while maintaining viability of intrinsic airway neurons. Pretreatment with CP-99994, an antagonist of neurokinin 1 receptor, attenuated the IL-1β-induced hyperreactivity to ACh and MCh and to EFS in cultured tracheal segments. SP-containing neurons in longitudinal trunk, SP innervation of superficial muscular plexus neurons, and SP nerve fiber density in tracheal smooth muscle all increased after treatment with IL-1β. These results show that IL-1β-enhanced cholinergic airway smooth muscle contractile responses are mediated by the actions of SP released from intrinsic airway neurons.

scholarly journals The role of substance P in depression: therapeutic implications

2002 ◽  
Vol 4 (1) ◽  
pp. 21-29 ◽  
Keyword(s):  
Major Depression ◽  
Substance P ◽  
Receptor Antagonist ◽  
Psychiatric Research ◽  
Double Blind Study ◽  
Significant Activity ◽  
Nk1 Receptor ◽  
Double Blind ◽  
Therapeutic Implications ◽  
Nk1 Receptor Antagonist

Substance P (for "powder"), identified as a gut tachykinin in 1931 and involved in the control of multiple other autonomic functions, notably pain transmission, is the focus of intense fundamental and clinical psychiatric research as a central neurotransmitter, neuromodulator, and immunomodulator, along with sister neurokinins A and B (NKA and NKB), discovered in 1984. Substance P is widely distributed throughout the central nervous system, where if is often colocalized with serotonin, norepinephrine, and dopamine. Many neurokinin (NK) receptor antagonists and agonists have been synthesized and some clinically tested. A double-blind study of MK869, a selective NK1 receptor antagonist that blocks the action of substance P, showed significant activity versus placebo and fewer sexual side effects than paroxetine in outpatients with major depression and moderate anxiety. Substance P, which is degraded by the angiotensin-converting enzyme (ACE), may mediate modulation of therapeutic outcome in affective disorders by functional polymorphism within the ACE gene: the D allele is associated with higher ACE levels and increased neuropeptide degradation, with the result that patients with major depression who carry the D allele have lower depression scores and shorter hospitalization. ACE polymorphism genotypinq might thus identify those patients with major depression likely to benefit from NK1 receptor antagonist therapy.

Upregulation of substance P receptors in angiogenesis associated with chronic airway inflammation in rats

1997 ◽  
Vol 273 (3) ◽  
pp. L565-L571 ◽  
Author(s):  
P. Baluk ◽  
J. J. Bowden ◽  
P. M. Lefevre ◽  
D. M. McDonald
Keyword(s):  
Endothelial Cells ◽  
Substance P ◽  
Blood Vessels ◽  
Sensory Nerves ◽  
Mycoplasma Pulmonis ◽  
Tracheal Mucosa ◽  
Fischer 344 ◽  
Nk1 Receptors ◽  
Plasma Leakage ◽  
Neurokinin 1

In rat airways, substance P released from sensory nerves induces plasma leakage via neurokinin-1 (NK1) receptors on endothelial cells. In pathogen-free rats, both leakage and endothelial NK1 receptors are most abundant in postcapillary venules. In Mycoplasma pulmonis-infected rats, extensive angiogenesis occurs in the tracheal mucosa. The capillary-sized (< 10 microns in diameter) angiogenic blood vessels are abnormally sensitive to substance P. The aim of this study was to determine whether increased expression of NK1 receptors contributes to this abnormal sensitivity. Fischer 344 rats were infected with M. pulmonis and were challenged with substance P (5 micrograms/kg i.v.), and then plasma leakage in the tracheal mucosa was measured by extravasation of Monastral blue (30 mg/kg i.v.). NK1 receptors on endothelial cells were localized by immunohistochemistry. Five minutes after substance P, NK1 receptor-immunoreactive endosomes were five times more abundant in endothelial cells of angiogenic capillaries in M. pulmonis-infected rats than in corresponding capillaries in pathogen-free controls (17.1 +/- 2.3 vs. 3.5 +/- 0.4 endosomes/100 micron 2 of endothelial surface). Endosomes were slightly more abundant in postcapillary venules 15-35 microns in diameter in infected rats (23.0 +/- 0.6 vs. 19.2 +/- 0.7 endosomes/100 micron 2). Similarly, after substance P, angiogenic capillaries had much more Monastral blue labeling (area density: 18.8 +/- 1.5 vs. 2.9 +/- 0.5% of vessel wall), whereas postcapillary venules had about the same amount of labeling (36.0 +/- 3.7 vs. 34.1 +/- 1.8%). We conclude that increased expression of NK1 receptors, which are internalized into endosomes after ligand binding, contributes to the abnormal sensitivity of endothelial cells of angiogenic blood vessels to substance P in the airways of M. pulmonis-infected rats.

Effect of Recombinant Neutral Endopeptidase (EC 3.4.24.11) on Neuropeptide-Mediated Nasal Fluid Secretion and Plasma Exudation in the Rat

1998 ◽  
Vol 12 (2) ◽  
pp. 135-142
Author(s):  
Malin Josefsson ◽  
Magnus Becker ◽  
Fritz Stroman ◽  
Daniel G. Brenner ◽  
Göran Petersson
Keyword(s):  
Substance P ◽  
Nasal Mucosa ◽  
Fluid Secretion ◽  
Neutral Endopeptidase ◽  
Sensory Nerves ◽  
Peptidase Activity ◽  
Experimental Conditions ◽  
Plasma Exudation ◽  
Nasal Fluid

The nasal mucosa harbors sensory nerves containing neuropeptides such as substance P (SP), which are released by capsaicin. The neuropeptides are degraded by peptidases, e.g., neutral endopeptidase (NEP) that is present in the nasal mucosa. We studied the effect of enzymatically active recombinant NEP (rNEP) on neuropeptide-evoked secretion of nasal fluid and plasma exudation in rats. rNEP administered intranasally (i.n.) reduced the capsaicin-evoked nasal fluid secretion but failed to reduce the secretion evoked by SP (exogenous) under the experimental conditions used. rNEP reduced the increase in nasal plasma exudation evoked by capsaicin (endogenous neuropeptides). Because rNEP reduced neuropeptide-mediated nasal fluid secretion and plasma exudation in the rat, we suggest that peptidase activity in the nasal mucosa will determine the magnitude of the response to locally released neuropeptides.

NK1 receptors mediate neurogenic inflammatory increase in blood flow in rat airways

1993 ◽  
Vol 74 (5) ◽  
pp. 2462-2468 ◽  
Author(s):  
G. Piedimonte ◽  
J. I. Hoffman ◽  
W. K. Husseini ◽  
R. M. Snider ◽  
M. C. Desai ◽  
...  
Keyword(s):  
Blood Flow ◽  
Substance P ◽  
Neurogenic Inflammation ◽  
Sensory Nerves ◽  
Nk1 Receptor ◽  
Nk1 Receptors ◽  
Calcitonin Gene ◽  
Nk1 Receptor Antagonist ◽  
Selective Agonists ◽  
Neurokinin 1

We studied the effect of neurogenic inflammation on airway blood flow in anesthetized F-344 rats. Three successive determinations of blood flow were made by injecting radionuclide-labeled microspheres suspended in 70% dextrose into the left ventricle. A selective agonist of the tachykinin receptor neurokinin 1 (NK1) increased airway blood flow, but NK2- and NK3-selective agonists were without effect. The natural agonist of NK1 receptors, substance P (1 micrograms/kg), increased airway blood flow, an effect that was abolished by the selective NK1 receptor antagonist CP-99,994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] but not by the (2R,3R)-enantiomer CP-100,263. Capsaicin (25 micrograms/kg), a drug that releases tachykinins and calcitonin gene-related peptide from sensory nerves, increased airway blood flow, and again this effect was abolished by CP-99,994. We also studied the effect of a selective inhibitor (captopril, 2.5 mg/kg) of the tachykinin-degrading enzyme kininase II [or angiotensin-converting enzyme (ACE)] on substance P-induced airway vasodilation. Captopril potentiated and prolonged the vasodilator effect of substance P. We conclude that neurogenic vasodilation in rat airways is due to the release of substance P, acts via NK1 receptors, and may be modulated by ACE.

scholarly journals Treatment of common warts with the immune stimulant Propionium bacterium parvum

2012 ◽  
Vol 87 (4) ◽  
pp. 585-589 ◽  
Author(s):  
Nilton Nasser
Keyword(s):  
Immune System ◽  
Mucous Membrane ◽  
Saline Solution ◽  
Immune Status ◽  
Intradermal Injection ◽  
The Other ◽  
Double Blind Study ◽  
Double Blind ◽  
Immune Modulator ◽  
Common Warts

BACKGROUND: Warts are epithelial proliferations in the skin and mucous membrane caused by various types of HPV. They can decrease spontaneously or increase in size and number according to the patient's immune status. The Propionium bacterium parvum is a strong immune stimulant and immune modulator and has important effects in the immune system and it is able to produce antibodies in the skin. OBJECTIVE: To show the efficacy of the Propionium bacterium parvum in saline solution in the treatment of skin warts. METHODS: A randomized double-blind study. Twenty patients with multiple warts were divided into two groups: one received 0,1ml intradermal injection of placebo solution in just one of the warts and the other received 0,1 ml of saline solution of Propionium bacterium parvum, one dose a month, for 3 to 5 months. RESULTS: Among the 20 patients who participated in the study, ten received the placebo and ten received the saline solution with Propionium bacterium parvum. In 9 patients treated with the Propionium bacterium parvum solution the warts disappeared without scars and in 1 patient it decreased in size. In 9 patients who received the placebo no change to the warts was observed and in 1 it decreased in size. CONCLUSIONS: The immune modulator and immune stimulant Propionium bacterium parvum produced antibodies in the skin which destroyed the warts without scars, with statistically significant results (P<0,001), and cured 90 % of the patients. We suggest the use of the immune stimulant in the treatment of warts.

scholarly journals Substance P inhibits pancreatic exocrine secretion via a neural mechanism

1999 ◽  
Vol 277 (2) ◽  
pp. G314-G320 ◽  
Author(s):  
Kimberly S. Kirkwood ◽  
Edward H. Kim ◽  
Xiao Dong He ◽  
Edna Q. Calaustro ◽  
Christopher Domush ◽  
...  
Keyword(s):  
Substance P ◽  
Pancreatic Juice ◽  
Neural Mechanism ◽  
Fluid Secretion ◽  
Exocrine Secretion ◽  
Sensory Nerves ◽  
Amylase Secretion ◽  
Perfused Rat Pancreas ◽  
Amylase Release ◽  
Neurokinin 1

We investigated the effects of the sensory neuropeptide substance P (SP) on amylase and fluid secretion in the isolated vascularly perfused rat pancreas. SP inhibited CCK-induced amylase release and secretin-induced juice flow via the pancreatic duct in a dose-related fashion. Threshold inhibition occurred following addition of 10−10 M SP to the perfusate, and maximal inhibition was seen with 10−8 M SP. The effects of SP were partially blocked by both the neurokinin-1 (NK1) and neurokinin-2 (NK2) receptor antagonists. Atropine and TTX blocked SP-induced effects on both amylase secretion (26 and 63% blockade, respectively) and pancreatic juice flow (21 and 79% blockade, respectively). Excitation of pancreatic sensory nerves using capsaicin (in the absence of SP) inhibited both amylase and pancreatic juice flow via activation of the NK1 receptor. We conclude that SP inhibits exocrine secretion via an indirect neural mechanism.

Respiratory syncytial virus upregulates expression of the substance P receptor in rat lungs

1999 ◽  
Vol 277 (4) ◽  
pp. L831-L840 ◽  
Author(s):  
Giovanni Piedimonte ◽  
Maria M. Rodriguez ◽  
Katherine A. King ◽  
Stafford McLean ◽  
Xiaobo Jiang
Keyword(s):  
Respiratory Syncytial Virus ◽  
Substance P ◽  
Inflammatory Responses ◽  
Receptor Gene ◽  
Neutral Endopeptidase ◽  
Sensory Nerves ◽  
Respiratory Pathogen ◽  
Target Cells ◽  
Mrna Levels ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is a major respiratory pathogen in infants. The first goal of this study was to determine whether the infection following endotracheal inoculation of RSV in Fischer 344 rats results in increased inflammatory responses to substance P (SP) either released by capsaicin from sensory nerves or injected into the circulation. Five days after inoculation, the extravasation of Evans blue-labeled albumin after capsaicin or SP was significantly greater in RSV-infected airways than in pathogen-free controls. The peptide-degrading activity of the regulatory enzyme neutral endopeptidase was unaffected by RSV. However, SP(NK1) receptor mRNA levels increased fivefold in RSV-infected lungs, and the density of SP binding sites in the bronchial mucosa increased threefold. These data suggest that RSV makes the airways abnormally susceptible to the proinflammatory effects of SP by upregulating SP(NK1) receptor gene expression, thereby increasing the density of these receptors on target cells. This effect may contribute to the inflammatory reaction to the virus and could be a target for the therapy of RSV disease and its sequelae.

Tachykinins, sensory nerves, and asthma—an overview

1995 ◽  
Vol 73 (7) ◽  
pp. 908-914 ◽  
Author(s):  
Jan M. Lundberg
Keyword(s):  
Viral Infections ◽  
Therapeutic Potential ◽  
Leukocyte Adhesion ◽  
Sensory Nerve ◽  
Neutral Endopeptidase ◽  
Sensory Nerves ◽  
Neurokinin A ◽  
Protein Extravasation ◽  
Neurokinin Receptor ◽  
Neurokinin 1

Tachykinin peptides, substance P (SP) and neurokinin A (NKA), are released from airway sensory nerves upon exposure to irritant chemicals and endogenous agents including bradykinin, prostaglandins, histamine, and protons. The released neuropeptides are potent inducers of a cascade of responses, including vasodilatation, mucus secretion, plasma protein extravasation, leukocyte adhesion–activation, and bronchoconstriction. Neurokinin 1 receptors (preferably activated by SP) seem to be most important for inflammatory actions, while neurokinin 2 receptors (preferably activated by NKA) mediate bronchoconstriction. Species differences exist whereby rat and guinea-pig have a more developed neurogenic inflammation response than normal human airways. However, disease states such as inflammation or viral infections lead to enhanced peptide synthesis and (or) increased sensory nerve excitability. Together with increased neurokinin 1 receptor synthesis and loss of major tachykinin-degrading enzymes such as neutral endopeptidase in airway inflammation, this suggests that recently developed, orally active nonpeptide neurokinin receptor antagonists could have a therapeutic potential in asthmatic patients.Key words: neurokinins, sensory nerves, inflammation, bronchoconstriction, receptors.

Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections

1989 ◽  
Vol 66 (6) ◽  
pp. 2653-2658 ◽  
Author(s):  
D. B. Borson ◽  
J. J. Brokaw ◽  
K. Sekizawa ◽  
D. M. McDonald ◽  
J. A. Nadel
Keyword(s):  
Substance P ◽  
Respiratory Tract ◽  
Neurogenic Inflammation ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Respiratory Infections ◽  
Neutral Endopeptidase ◽  
Sensory Nerves ◽  
Mycoplasma Pulmonis ◽  
Tract Infections

Neuropeptides such as substance P are implicated in inflammation mediated by sensory nerves (neurogenic inflammation), but the roles in disease of these peptides and the peptidases that degrade them are not understood. It is well established that inflammation is a prominent feature of several airway diseases, including viral infections, asthma, bronchitis, and cystic fibrosis. These diseases are characterized by cough, airway edema, and abnormal secretory and bronchoconstrictor responses, all of which can be elicited by substance P. The effects of substance P and other peptides that may be involved in inflammation are decreased by endogenous neutral endopeptidase (NEP; also called enkephalinase, EC 3.4.24.11), which is a peptidase that degrades substance P and other peptides. In the present study, we report that rats with histories of infections caused by common respiratory tract pathogens (parainfluenza virus type 1, rat corona-virus, and Mycoplasma pulmonis) not only have greater susceptibility to neurogenic inflammatory responses than do pathogen-free rats but also have a lower activity of NEP in the trachea. This reduction in NEP activity may cause the increased susceptibility to neurogenic inflammation by allowing higher concentrations of substance P to reach tachykinin receptors in the trachea. Thus decreased NEP activity may exacerbate some of the pathological responses in animals with respiratory tract infections.

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