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The Effect Of The Nitric Oxide Synthase Inhibitor N-Nitro-L-Arginine-Methyl Ester On Neuropeptide-Induced Vasodilation And Protein Extravasation In Human Skin
M. Klede, G. Clough, G. Lischetzki, M. Schmelz
Published 2003 · Medicine, Chemistry
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Endogenous neuropeptides released from nociceptors can induce vasodilation and enhanced protein extravasation (neurogenic inflammation). The role of nitric oxide (NO) in the induction of neurogenic inflammation is controversial. In this study, dermal microdialysis was used in awake humans (n = 39) to deliver substance P (SP; 10–7 and 10–6M) or calcitonin gene-related peptide (CGRP; 5 × 10–7M and 2 × 10–6M). Neuropeptide-induced local and axon reflex erythema was assessed by laser Doppler imaging. Total protein concentration in the dialysate was measured to quantify local protein extravasation. The responses were assessed in the absence and the presence of the nitric oxide synthase inhibitor, N-nitro-L-arginine-methyl ester (L-NAME) added to the perfusate at concentrations of 5, 10 or 20 mM. L-NAME (5 mM) applied via the dialysis catheters reduced local blood flow by approximately 30%. In addition, L-NAME inhibited SP-induced vasodilation by about 40% for 10–7M SP and 30% for 10–6M SP (n = 11, p < 0.01). In contrast, CGRP-induced vasodilation was only marginally inhibited by L-NAME. SP, but not CGRP, provoked a dose-dependent increase in protein extravasation. L-NAME (5 mM) inhibited this increase by up to 40% for both SP concentrations used (n = 11, p < 0.01). Higher concentrations of L-NAME did not further reduce SP- or CGRP-induced vasodilation or SP-induced protein extravasation. Exogenously applied SP induces vasodilation and protein extravasation, which is partly NO mediated, whereas CGRP-induced vasodilation appears to be NO independent.
This paper references
Comparison of forearm vasodilatation to substance P and acetylcholine: contribution of nitric oxide.
D. Newby (1997)
Participation of nitric oxide in the mustard oil-induced neurogenic inflammation of the rat paw skin.
I. Lippe (1993)
Nitric oxide donors enhance calcitonin gene-related peptide-induced elevations of cyclic AMP in vascular smooth muscle cells.
L. F. Lu (1999)
Inhibition by hydroxyl radicals of calcitonin gene-related peptide-mediated neurogenic vasorelaxation in isolated canine lingual artery.
M. Norisue (1997)
Nitric oxide‐dependent release of vasodilator quantities of calcitonin gene‐related peptide from capsaicin‐sensitive nerves in rabbit skin
S. Hughes (1994)
Endogenous nitric oxide: physiology, pathology and clinical relevance
S. Moncada (1991)
Substance P and inflammatory pain: potential of substance P antagonists as analgesics.
J. Henry (1993)
Lack of Nitric Oxide Mediation of Flow-Dependent Arteriolar Dilation in Type I Diabetes Is Restored by Sepiapterin
Zsolt Bagi (2003)
Mast cell tryptase in dermal neurogenic inflammation
Primary afferent tachykinins are required to experience moderate to intense pain
Yu Cao (1998)
Pain, Tenderness, Wheal and Flare Induced by Substance-P, Bradykinin and 5-Hydroxytryptamine in Humans
K. Jensen (1991)
Multiple nitric oxide sources in neurogenic plasma extravasation in rat hindpaw skin.
M. Szikszay (1998)
Involvement of substance P but not nitric oxide or calcitonin gene-related peptide in neurogenic plasma extravasation in rat incisor pulp and lip.
N. Kerezoudis (1994)
Calcitonin gene-related peptide acts as a novel vasodilator neurotransmitter in mesenteric resistance vessels of the rat
Hiromu Kawasaki (1988)
Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems
T. Scholzen (1998)
Acute effects of substance P and calcitonin gene-related peptide in human skin--a microdialysis study.
C. Weidner (2000)
The tachykinin NK1 receptor. Part I: Ligands and mechanisms of cellular activation
L. Quartara (1997)
Evidence of a role for NK1 and CGRP receptors in mediating neurogenic vasodilatation in the mouse ear
A. Grant (2002)
Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors.
J. Vásquez-Vivar (1998)
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
M. M. Bradford (1976)
Endothelium and the vasodilator action of rat calcitonin gene‐related peptide (CGRP)
G. Grace (1987)
Pharmacological properties of a potent and selective nonpeptide substance P antagonist.
C. Garret (1991)
Neuropeptides in the skin of patients with atopic dermatitis
L. Ostlere (1995)
cGMP-Mediated Facilitation in Nerve Terminals by Enhancement of the Spike Afterhyperpolarization
V. Klyachko (2001)
Neurally-mediated vasodilatation in normal and portal hypertensive rats: role of nitric oxide and calcitonin gene-related peptide.
C. Moll-Kaufmann (1998)
Potent vasodilator activity of calcitonin gene-related peptide in human skin.
S. Brain (1986)
Inhibition of neurogenic vasodilation and plasma extravasation by substance P antagonists, somatostatin and [D-Met2, Pro5]enkephalinamide.
F. Lembeck (1982)
Role of nitric oxide towards vasodilator effects of substance P and ATP in human forearm vessels.
M. Shiramoto (1997)
cGMP and S-nitrosylation: two routes for modulation of neuronal excitability by NO
G. Ahern (2002)
Inflammatory oedema induced by synergism between calcitonin gene‐related peptide (CGRP) and mediators of increased vascular permeability
S. Brain (1985)
Diverse interactions of calcitonin gene related peptide and nitric oxide in the gastric and cutaneous microcirculation.
P. Holzer (1995)
α‐adrenergic supersensitivity of the sudomotor nerve in complex regional pain syndrome
K. Chémali (2001)
Role of nitric oxide in the regulation of microvascular perfusion in human skin in vivo
G. Clough (1999)
Neuropeptides induce release of nitric oxide from human dermal microvascular endothelial cells.
H. Bull (1996)
Substance P induction of itch-associated response mediated by cutaneous NK1 tachykinin receptors in mice.
T. Andoh (1998)
Vasodilatation by calcitonin gene-related peptide and by substance P: a comparison of their effects on resistance and capacitance vessels of human forearms.
J. Mcewan (1988)
Attenuation of human nasal airway responses to bradykinin and histamine by inhibitors of nitric oxide synthase
J. Dear (1996)
Essential role for nitric oxide in neurogenic inflammation in rat cutaneous microcirculation. Evidence for an endothelium-independent mechanism.
R. Kajekar (1995)
Visualization of nitric oxide formation in cell cultures and living tissue.
N. Wiklund (1999)
Inhibitors of nitric oxide synthase in human skin.
P. Goldsmith (1996)
CGRP and nitric oxide of neuronal origin and their involvement in neurogenic vasodilatation in rat skin microvasculature
M. Merhi (1998)
Effects of substance P, neurokinin A and calcitonin gene-related peptide in human skin and their involvement in sensory nerve-mediated responses.
J. Wallengren (1987)
Quantitative determination of endogenous nitric oxide in the mouse skin in vivo by microdialysis.
T. Andoh (1997)
Evidence for a Differential Cellular Distribution of Inward Rectifier K Channels in the Rat Isolated Mesenteric Artery
G. Crane (2003)
Highly Effective Non-Viral Gene Transfer into Vascular Smooth Muscle Cells of Cultured Resistance Arteries Demonstrated by Genetic Inhibition of Sphingosine-1-Phosphate-Induced Vasoconstriction
S. Bolz (2003)
The contribution of calcitonin gene-related peptide (CGRP) to neurogenic vasodilator responses
S. Brain (2005)
Persistence of effects of nitric oxide synthase inhibitors: comparisons on blood flow and plasma exudation in guinea pig skin.
A. Pérez (1997)
Inducible Nitric-oxide Synthase Generates Superoxide from the Reductase Domain*
Y. Xia (1998)
Neurogenic vasodilatation and plasma leakage in the skin.
P. Holzer (1998)
Superoxide in the Vascular System
M. Wolin (2002)
Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries.
T. Matoba (2002)
Role of endogenous nitric oxide in airway microvascular leakage induced by inflammatory mediators.
N. Kageyama (1997)
Role of nitric oxide in the actions of substance P and other mediators of inflammation in rat skin microvasculature.
V. Ralevic (1995)
Demonstration of a ‘septide‐sensitive’ inflammatory response in rat skin
A. Ahluwalia (1995)
Ocular inflammation induced by electroconvulsive treatment: contribution of nitric oxide and neuropeptides mobilized from C‐fibres
Z. Wang (1997)
Bradykinin and changes in microvascular permeability in the hamster cheek pouch: role of nitric oxide
M. Félétou (1996)
Nitric oxide and sensory nerves are involved in the vasodilator response to acetylcholine but not calcitonin gene‐related peptide in rat skin micro vasculature
V. Ralevic (1992)
Neurogenic oedema and vasodilatation: effect of a selective neuronal NO inhibitor
P. K. Towler (1998)
This paper is referenced by
Maximum Skin Hyperaemia Induced by Local Heating: Possible Mechanisms
K. Gooding (2006)
Neuropeptides in the Skin
J. Baraniuk (2004)
Retrograde tracing of spinal cord connections to the cervix with pregnancy in mice.
M. A. Kirby (2010)
Nicotine increases initial blood flow responses to local heating of human non‐glabrous skin
D. Warner (2004)
Altered thermal hyperaemia in human skin by prior desensitization of neurokinin‐1 receptors
B. J. Wong (2011)
Neurokinin‐1 receptor desensitization attenuates cutaneous active vasodilatation in humans
B. J. Wong (2006)
Skin microdialysis: methods, applications and future opportunities—an EAACI position paper
Katrine Baumann (2019)
Neurokinin‐1 receptor desensitization to consecutive microdialysis infusions of substance P in human skin
B. J. Wong (2005)
Recovery of Nitric Oxide from Acetylcholine‐Mediated Vasodilatation in Human Skin In Vivo
P. Boutsiouki (2004)
Evidence of enhanced non-enzymatic generation of nitric oxide on the skin surface of acupuncture points: An innovative approach in humans.
S. Ma (2007)
Retrograde tracing of spinal cord connections to
Michael A. Kirby (2009)
The effect of microdialysis needle trauma on cutaneous vascular responses in humans.
G. Hodges (2009)
A Qualitative and Quantitative Proteomic Study of Human Microdialysate and the Cutaneous Response to Injury
C. Gill (2011)
Perioperative Abstinence from Cigarettes: Physiologic and Clinical Consequences
D. Warner (2006)
New approach to measure cutaneous microvascular function: an improved test of NO-mediated vasodilation by thermal hyperemia.
Patricia J. Choi (2014)
Preserved reflex cutaneous vasodilation in cystic fibrosis does not include an enhanced nitric oxide-dependent mechanism.
B. W. Wilkins (2007)
Controlled dermal cell damage as human in vivo model for localised pain and inflammation
I. Fairweather (2003)
The role of the Transient Receptor Potential Ankyrin-1 in the peripheral vasculature
Aisah A Aubdool (2014)
Neuronal nitric oxide synthase in epidermis is involved in cutaneous circulatory response to mechanical stimulation.
K. Ikeyama (2010)
The role of endothelial nitric oxide in the Substance P induced vasodilation in bovine dental pulp.
B. Karabucak (2005)
Mechanisms of vasoactive intestinal peptide-mediated vasodilation in human skin.
B. W. Wilkins (2004)
Use of sensory methods for detecting target engagement in clinical trials of new analgesics
B. Chizh (2011)
An effective method for skin blood flow measurement using local heat combined with electrical stimulation
A-M R Almalty (2009)
Microdialysis of large molecules
G. Clough (2008)
Chapter 3 Nociceptors: neurogenic inflammation.
H. Handwerker (2006)
humansthermal hyperemia to local heating in
Brett J Wong (2015)
Neuropeptide (calcitonin gene-related peptide) induction of nitric oxide in human keratinocytes in vitro.
Y. E (2006)
Sensory nerves and nitric oxide contribute to reflex cutaneous vasodilation in humans.
B. J. Wong (2013)
Hypothesis Testing of the “ Neurogenic Inflammation Theory of Migraine ” : Selective Inhibition of Dural PPE
S. Peroutka (2005)
Acerca do impacto da administração transdérmica de um inibidor da NO-sintetase (L-NAME) : uma abordagem preliminar
P. Pinto (2009)
Shared Fate of Meningeal Mast Cells and Sensory Neurons in Migraine
Duygu Koyuncu Irmak (2019)
Using objective markers and imaging in the development of novel treatments of chronic pain
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