A reactive oxygen species-mediated component in neurogenic vasodilatation

Starr, Anna; Graepel, Rabea; Keeble, Julie; Schmidhuber, Sabine; Clark, Natalie; Grant, Andrew; Shah, Ajay M.; Brain, Susan D.

doi:10.1093/cvr/cvn012

Cited by 60 publications

(69 citation statements)

References 41 publications

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“…The exception was the animals that were injected (i.p.) with 5 mg/kg Win51708 (Sigma-Aldrich, St. Louis, MO) dissolved in 10% dimethylsulfoxide (DMSO) (10 mg/ml) 10 minutes before each measurement or/and in case of BIBN4096BS (Boehringer Ingelheim Pharma KG, Biberach, Germany) dissolved in 10% DMSO, 0.3mg/kg (the dose was based on Doods et al, 2000;Just et al, 2005;Starr et al, 2008) 30 minutes before each measurement using the Hargreaves setup or von Frey filaments. No injections of Win51708 or BIBN4096BS were made before the 30-minute measurement.…”

Section: Neurotransmitters In Inflammation-induced Hyperalgesiamentioning

confidence: 99%

Glutamate, Substance P, and Calcitonin Gene-Related Peptide Cooperate in Inflammation-Induced Heat Hyperalgesia

et al. 2013

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The transient receptor potential cation channel subfamily V member 1 (TRPV1) is known as a thermosensor and integrator of inflammation-induced hyperalgesia. TRPV1 is expressed in a subpopulation of primary afferent neurons that express several different neurotransmitters. The role of the TRPV1 channel in the development of hyperalgesia is established, but the role of the neurotransmitter glutamate, used partially by the same neuronal population and thus probably mediating the response, is still under investigation. We have used a Trpv1-Cre mouse line in which we either ablated Trpv1-Cre expressing neurons or induced vesicular glutamate transporter 2 (Vglut2) deficiency in Trpv1-Cre expressing neurons and investigated specific states of hyperalgesia after persistent inflammation. Furthermore, by pharmacologic inhibition of substance P (SP) or calcitonin gene-related peptide (CGRP) signaling in Vglut2-deficient mice, we also evaluated the contribution of SP or CGRP to inflammationinduced hyperalgesia, with or without the presence of vesicular glutamate transporter 2 (VGLUT2)-mediated glutamatergic transmission in Trpv1-Cre neurons. This examination, together with c-Fos analyses, showed that VGLUT2-mediated glutamatergic transmission in Trpv1-Cre afferents together with SP or CGRP is essential for the development of the heat hyperalgesia associated with persistent inflammation. Additionally, SP-, CGRP-, and VGLUT2-mediated transmission together were found to play a role in the development of mechanical hyperalgesia after persistent inflammation.

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Section: Neurotransmitters In Inflammation-induced Hyperalgesiamentioning

confidence: 99%

Glutamate, Substance P, and Calcitonin Gene-Related Peptide Cooperate in Inflammation-Induced Heat Hyperalgesia

et al. 2013

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“…17,18 We have investigated the AngII hypertension model in wild-type (WT) and αCGRP knockout (αCGRPKO) mice that have similar resting BP. We hypothesized that αCGRP is protective against the onset and development of hypertension, and the aim was to identify mechanisms by which αCGRP is protective in this model.…”

mentioning

confidence: 99%

An Ongoing Role of α-Calcitonin Gene–Related Peptide as Part of a Protective Network Against Hypertension, Vascular Hypertrophy, and Oxidative Stress

et al. 2014

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1056α -Calcitonin gene-related peptide (αCGRP) is a potent vasodilator 1 and a hypotensive peptide. It is primarily localized to the sensory nervous system, with a perivascular innervation and considered to be the major cardiovascular form, as compared with the structurally similar βCGRP. CGRP acts via a G-protein-coupled receptor (calcitonin-like receptor) when dimerized with a single transmembrane-spanning receptor activity-modifying protein RAMP1 2 signaling via cAMP and other pathways. 3,4 CGRP does not play a primary role in the regulation of basal blood pressure (BP) in normal individuals 5,6 but is suggested to have protective properties, in cardiovascular disease, 7,8 including attenuation of vascular smooth muscle proliferation, 9 hyperplasia, 10,11 and stimulation of endothelial cell proliferation 12 and endothelial progenitor cells. 13 Evidence indicates the importance of CGRP in aggressive models of rodent hypertension that are centered on the kidney. 14,15 By comparison, there is little evidence of detailed analysis involving the ongoing influence of endogenous CGRP on hypertensive mechanisms and vascular remodeling, especially with regard to NO and oxidative stress pathways.Sensory nerve-derived CGRP release is stimulated by mechanisms that include angiotensin II (AngII) and sympathetic nerve reflexes, 3,4 baroreflex sensitivity, 16 and sensory nerve activators. 17,18 We have investigated the AngII hypertension model in wild-type (WT) and αCGRP knockout (αCGRPKO) mice that have similar resting BP. We hypothesized that αCGRP is protective against the onset and development of hypertension, and the aim was to identify mechanisms by which αCGRP is protective in this model. The novel findings show Abstract-α-Calcitonin gene-related peptide (αCGRP) is a vasodilator, but there is limited knowledge of its long-term cardiovascular protective influence. We hypothesized that αCGRP protects against the onset and development of angiotensin II-induced hypertension and have identified protective mechanisms at the vascular level. Wild-type and αCGRP knockout mice that have similar baseline blood pressure were investigated in the angiotensin II hypertension model for 14 and 28 days. αCGRP knockout mice exhibited enhanced hypertension and aortic hypertrophy. αCGRP gene expression was increased in dorsal root ganglia and at the conduit and resistance vessel level of wild-type mice at both time points. βCGRP gene expression was also observed and shown to be linked to plasma levels of CGRP. Mesenteric artery contractile and relaxant responses in vitro and endothelial NO synthase expression were similar in all groups. The aorta exhibited vascular hypertrophy, increased collagen formation, and oxidant stress markers in response to angiotensin II, with highest effects observed in αCGRP knockout mice. Gene and protein expression of endothelial NO synthase was lacking in the aortae after angiotensin II treatment, especially in αCGRP knockout mice. These results demonstrate the ongoing upregulation of αCGRP at the levels...

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“…We have shown previously that activation of TRPV1 by capsaicin triggers neurogenic vasodilatation in the mouse in vivo (Grant et al, 2002;Starr et al, 2008). Unlike mustard oil and capsaicin, 4-ONE cannot be prepared for topical administration and was therefore injected intraplantarly.…”

Section: Discussionmentioning

confidence: 99%

“…Female CD1 mice (25-30 g) were purchased from Charles River (Margate, Kent, UK). We used age-and sex-matched male and female wild-type (WT) and TRPV1 knockout (KO) mice on a C57BL6/129SVJ strain (Clark et al, 2007) as well as WT and TRPA1 KO mice on a mixed genetic background as described previously (Kwan et al, 2006;Andersson et al, 2008;Starr et al, 2008) and WT and CGRP KO mice on a C57BL/6 strain (Grant et al, 2005;Starr et al, 2008); all mice were bred in-house. Mice were housed in a climatically controlled environment, maintained on a 12:12-h light/dark cycle, with access to food and water ad libitum.…”

Section: Methodsmentioning

confidence: 99%

4-Oxo-2-nonenal (4-ONE): Evidence of Transient Receptor Potential Ankyrin 1-Dependent and -Independent Nociceptive and Vasoactive Responses In Vivo

Graepel

Fernandes²,

Aubdool

et al. 2011

J Pharmacol Exp Ther

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This study explores the in vivo effects of the proposed transient receptor potential ankyrin 1 (TRPA1) agonist 4-oxo-2-nonenal (4-ONE). Pharmacological inhibitors and genetically modified mice were used to investigate the ability of 4-ONE to act via TRPA1 receptors and possible mechanisms involving transient receptor potential vanilloid 1 (TRPV1). We hypothesized that 4-ONE activates sensory nerves, via TRPA1 or possibly TRPV1, and thus triggers mechanical hyperalgesia, edema formation, and vasodilatation in mice. An automated dynamic plantar aesthesiometer was used to determine hind paw withdrawal thresholds, and a laser Doppler flowmeter was used to measure skin blood flow. Edema formation was determined by measuring paw weights and thickness. 4-ONE (10 nmol) triggers unilateral mechanical hyperalgesia, edema formation, and vasodilatation in mice and is shown here to exhibit TRPA1-dependent and -independent effects. Neurogenic vasodilatation and mechanical hyperalgesia at 0.5 h postinjection were significantly greater in TRPA1 wild-type (WT) mice compared with TRPA1 knockout (KO) mice. Edema formation throughout the time course as well as mechanical hyperalgesia from 1 to 4 h postinjection were similar in WT and TRPA1 KO mice. Studies involving TRPV1 KO mice revealed no evidence of TRPV1 involvement or interactions between TRPA1 and TRPV1 in mediating the in vivo effects of 4-ONE. Previously, 4-ONE was shown to be a potent TRPA1 agonist in vitro. We demonstrate its ability to mediate vasodilatation and certain nociceptive effects in vivo. These data indicate the potential of TRPA1 as an oxidant sensor for vasodilator responses in vivo. However, 4-ONE also triggers TRPA1-independent effects that relate to edema formation and pain.

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A reactive oxygen species-mediated component in neurogenic vasodilatation

Cited by 60 publications

References 41 publications

Glutamate, Substance P, and Calcitonin Gene-Related Peptide Cooperate in Inflammation-Induced Heat Hyperalgesia

Glutamate, Substance P, and Calcitonin Gene-Related Peptide Cooperate in Inflammation-Induced Heat Hyperalgesia

An Ongoing Role of α-Calcitonin Gene–Related Peptide as Part of a Protective Network Against Hypertension, Vascular Hypertrophy, and Oxidative Stress

4-Oxo-2-nonenal (4-ONE): Evidence of Transient Receptor Potential Ankyrin 1-Dependent and -Independent Nociceptive and Vasoactive Responses In Vivo

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