The Neurogenic Vasodilator Response to Endothelin‐1: A Study in Human Skin <i>In Vivo</i>

Katugampola, Ruwani; Church, Martin K.; Clough, Geraldine F.

doi:10.1111/j.1469-445x.2000.02089.x

Cited by 53 publications

(30 citation statements)

References 33 publications

(50 reference statements)

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“…This result corroborates studies in spinothalamic tract neurons in the monkey, showing a strikingly similar pattern of two nonoverlapping populations being activated by either histamine or cowhage (Davidson et al 2007). Interestingly, this type of dichotomous response was also found for endothelin, which provoked "burning itch" on intradermal application (Katugampola et al 2000) and activated the majority of polymodal nociceptors but no CMi fibers in humans (Namer et al 2007). …”

Section: Discussionmentioning

confidence: 99%

Separate Peripheral Pathways for Pruritus in Man

Namer¹,

Carr²,

Johanek³

et al. 2008

Journal of Neurophysiology

235

249

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Recent findings suggest that itch produced by intradermal insertion of cowhage spicules in human is histamine independent. Neuronal mechanisms underlying nonhistaminergic itch are poorly understood. To investigate which nerve fibers mediate cowhage induced itch in man, action potentials were recorded from cutaneous C-fibers of the peroneal nerve in healthy volunteers using microneurography. Mechano-responsive and -insensitive C-nociceptors were tested for their responsiveness to cowhage spicules, histamine, and capsaicin. Cowhage spicules induced itching and activated all tested mechano-responsive C-units (24/24, but no mechano-insensitive C-fibers (0/17). Histamine also induced itch, but in contrast to cowhage, it caused lasting activation only in mechano-insensitive units (8/12). In mechano-responsive C-units, histamine caused no or only short and weak responses unrelated to the time course of itching. Capsaicin injections activated four of six mechano-responsive fibers and three of four mechano-insensitive C-fibers. Cowhage and histamine activate distinctly different nonoverlapping populations of C-fibers while inducing similar sensations of itch. We hypothesize that cowhage activates a pathway for itch that originates peripherally from superficial mechano-responsive (polymodal) C-fibers and perhaps other afferent units. It is distinct from the pathway for histamine-mediated pruritus and does not involve the histamine-sensitive mechano-insensitive fibers.

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Section: Discussionmentioning

confidence: 99%

Separate Peripheral Pathways for Pruritus in Man

Namer¹,

Carr²,

Johanek³

et al. 2008

Journal of Neurophysiology

235

249

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“…Upon stimulation, mast cells, endothelial cells, and sensory nerves can release ET-1 (22)(23)(24)(25). ET-1 has been described as a pain mediator (60), but is also a potent itch inducer in murine and human skin (14,27,28,33). ET-1 is involved in mast cell-dependent inflammation by release of mediators such as histamine and leukotriene C4 (61)(62)(63)(64).…”

Section: Discussionmentioning

confidence: 99%

“…ET-1 is a potent vasoconstrictor that can also evoke pain sensations in rodents and humans (14,22,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). The biological effects of ET-1 are mediated by two distinct GPCRs: endothelin A receptor (ETAR) and endothelin B receptor (ETBR) (37).…”

Section: Introductionmentioning

confidence: 99%

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

et al. 2014

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In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.

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“…10 Here, we tested whether ET-1 is one of the signals involved in the elicitation of inflammatory responses after UVB irradiation by combined pharmacological and ge-…”

Section: Endothelin (Et-1) Has Been Shown To Crucially Contribute To mentioning

confidence: 99%

“…9 Second, intracutaneous injections of ET-1 reportedly trigger inflammatory reactions, including a pronounced flare response associated with sensations of a burning itch, a classic symptom of a UV-induced inflammatory response. 10 Here, we tested whether ET-1 is one of the signals involved in the elicitation of inflammatory responses after UVB irradiation by combined pharmacological and ge-netic approaches using highly selective and specific ET-1 receptor antagonists and using mutant mouse models. Our results reveal ET-1 as an important player in UV-induced inflammation and identify mast cells as one of the crucial cellular components of the underlying mechanism of this novel function of ET-1.…”

mentioning

confidence: 99%

Inflammatory Murine Skin Responses to UV-B Light Are Partially Dependent on Endothelin-1 and Mast Cells

Metz¹,

Lammel²,

Gibbs

et al. 2006

The American Journal of Pathology

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Endothelin (ET-1) has been shown to crucially contribute to UV-induced skin responses such as tanning.To test whether ET-1 is also involved in early cutaneous reactions to UV, we assessed ET-1 skin levels in UV-irradiated mice. In correlation with the levels of UV-induced skin inflammation, ET-1 concentrations increased substantially and continually. Moreover, blocking of ET-1 receptors (ET A ) resulted in significantly decreased cutaneous inflammation following UV irradiation. When we assessed skin responses to ET-1 injections, we observed prominent mast cell degranulation and mast cell-dependent inflammation. Since mast cells also critically contributed to UV-induced inflammation, we determined the ET-1-dependent inflammatory response to UV in the absence and presence of these cells. Interestingly, ET A blockade did not decrease UV-induced inflammation in mast cell-deficient mice, unless these mice had been adoptively transferred with mast cells before irradiation. This indicates that skin inflammation due to UV irradiation is caused in part by ET-1 acting on skin mast cells. Immediate skin responses following exposure to sunlight are largely mediated by UV-B light (UVB): low to moderate doses of UVB result in tanning, whereas intense UVB irradiation also gives rise to considerable inflammation, ie, solar dermatitis. UVB-induced tanning is widely regarded to result from the up-regulation of pigment production in epidermal melanocytes, which is induced by melanogens released from activated keratinocytes. In contrast, the cellular and molecular mechanisms involved in the induction of inflammatory skin responses to UVB are largely unknown.Recently, the vasoconstrictor peptide endothelin-1 (ET-1), one of the melanogens that contributes to UVBinduced tanning, 1,2 was found to promote inflammation in various pathological processes. For example, we and others have recently shown that ET-1 levels are up-regulated in murine septic peritonitis and that elevated ET-1 levels contribute to morbidity and mortality in this setting.3,4 Increased ET-1 production and mRNA expression have been demonstrated in lung tissue and bronchoalveolar lavage fluid in different models of airway inflammation. [5][6][7] In addition, elevated ET-1 concentrations are also present in patients with systemic lupus erythematosus, Takayasu arteritis, or Raynaud's phenomenon, where, in the latter case, the increase was shown clearly to contribute to disease severity. 8 These observations indicate that ET-1, in addition to having stimulatory effects on melanocytes, may orchestrate the induction of inflammatory responses after UVB irradiation. Two recent reports support this notion. First, the expression of ET-1 and its receptors ET A and ET B in murine skin was found to be markedly and rapidly upregulated after UVB irradiation, both in the dermis and epidermis.9 Second, intracutaneous injections of ET-1 reportedly trigger inflammatory reactions, including a pronounced flare response associated with sensations of a burning itch, a classic symptom of a ...

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The Neurogenic Vasodilator Response to Endothelin‐1: A Study in Human Skin In Vivo

Cited by 53 publications

References 33 publications

Separate Peripheral Pathways for Pruritus in Man

Separate Peripheral Pathways for Pruritus in Man

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

Inflammatory Murine Skin Responses to UV-B Light Are Partially Dependent on Endothelin-1 and Mast Cells

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