ME/CFS, POTS - carotid body and gasotransmitters

The hallmark of Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is post exertional malaise (PEM). Research shows that if ME/CFS patients exercise on two consecutive days, they are unable to reproduce their day 1 performance on day 2. VO(2) max is significant lower on day 2. Reference.

The autonomic dysfunction Postural Orthostatic Tachycardia Syndrome (POTS) is a common ME/CFS comorbidity.

Both ME/CFS and POTS may have dysregulation of H(2)S and NO.

I think it is time to take a closer look at the carotid body:

The carotid body is a small cluster of chemoreceptors and supporting cells located near the fork of the carotid artery, which runs along both sides of the throat.

The carotid body functions as a sensor:

• Carotid body monitors the blood’s pH, pCO2, and pO2 and thereby modulates cardiovascular and respiratory function primarily through sympathetic tone. 
• When the carotid body senses acidemia, hypercapnea, or hypoxia, autonomic firing leads to increased blood pressure, heart rate, and respiratory rate.
• The function of the carotid body is complemented by other chemoreceptors, most notably the aortic body located in the aortic arch.

As there are no research in carotid body function in ME/CFS/POTS, we must look elsewhere for information: Role of neurotransmitter gases in the control of the carotid body in heart failure: This review highlights evidence that the alterations in the gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide in the carotid body contribute to the exaggerated carotid body function observed in heart failure. And the paper informs us, that these gas transmitter effects carry important clinical relevance given the importance of the carotid body in the genesis and maintenance of autonomic imbalance and breathing instability in heart failure.

Does alteration in the gasotransmitters in the carotid body contribute to ME/CFS/POTS? Is a possible alteration a result of hypoxia (exercise intolerance)?

Further knowledge here, Hydrogen sulfide as an oxygen sensor:  Cellular H2S production is inversely related to pO2. The author of this paper, Professor of Physiology Kenneth Olson, is to be found at Indiana University, and he emphasises: "Our research has shown that the oxygen sensing mechanism consists of a delicate balance between constitutive production of biologically active H2S in the cell and its oxidation (destruction) by the cell’s mitochondria. Thus the concentration of this important signaling molecule is inversely and inexorably coupled to oxygen availability."

Interesting observation:

It is interesting to notice that Stress peptide PACAP engages multiple signaling pathways within the carotid body to initiate excitatory responses in respiratory and sympathetic chemosensory afferents.

..because the receptor for the stress peptide PACAP has increased expression in ME/CFS patients:

"Compared to healthy individuals, CFS/ME patients displayed significant increases in VPACR2 expression" from this paper Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Update 15. juni 2014: Problems with measurement of H2S: Controversies and Conundrums in Hydrogen Sulfide Biology

Further reading:

VIP and PACAP

Gasotransmitter regulation of ion channels: a key step in O2 sensing by the carotid body
The Carotid Body as a Therapeutic Target for the Treatment of Sympathetically Mediated Diseases

Basic knowledge NO - H(2)S - CO interaction - where to begin.

If dysregulation of NO and H(2)S is involved in ME/CFS and POTS, I would like to get som basic knowledge about how these parameters interact. 

Where do you start, if you don't now anything?  I started here: Nitric Oxide: Biology and Chemistry 

The journal have recently emphasized the importance of understanding the interaction between NO, H(2)S and CO: Embracing sulfide and CO to understand nitric oxide biology

Quote from this paper: "The availability of NO is dependent on the relative rates of NO formation and trapping by oxygenated hemes, co-generated reactive oxygen species and perhaps H2S. Thus, the formation of secondary reactive nitrogen oxide species such as peroxynitrite (ONOO−), nitrogen dioxide (NO2), and dinitrogen trioxide (N2O3) all depends on the relative flux rates of generation of individual reactants, nearby antioxidant enzyme expression/activity, and even the presence of carbon dioxide/bicarbonate (CO2/HCO3−)."

Remember that availability of NO is discussed in ME.

And dysregulation of H(2)S in ME and POTS is also a subject. 

The paper mentioned above refers to this review: Chemical foundations of hydrogen sulfide biology:

• This review includes the basic physical and chemical properties of H(2)S and H(2)S chemistry.
• This review focuses on the chemical foundations of H(2)S biology and methodology.
• This review introduces standard terminology to the H(2)S field.
• This review calls attention to chemical misconceptions in the studies of H(2)S.

and to this paper Hydrogen sulfide chemical biology: Pathophysiological roles and detection:

• H(2)S chemical biology and pathophysiology are rapidly evolving fields.
• Accurate H(2)S detection is crucial for understanding its biological roles.
• H(2)S interactions with gasotransmitters, e.g., NO, uniquely regulate tissue function.

Since gut dysfunction and the microbiome also are important issues in ME, this article also seems to be important: Microbial regulation of host hydrogen sulfide bioavailability and metabolism: 

• H(2)S in its various biochemical forms differs significantly between tissues.
• The microbiota affects H(2)S bioavailability in tissue and plasma.
• The microbiota alters cystathionine γ-lyase activity and cysteine bioavailability.

Update 15. juni 2014: Problems with measurement of H2S: Controversies and Conundrums in Hydrogen Sulfide Biology

ME, POTS, H(2)S, NO - hvad er sammenhængen?

I min sidste blogpost skrev jeg om mulig sammenhæng mellem hydrogensulfid, ME, POTS og TRPA1. Nu vil jeg kigge nærmere på en interessant sammenhæng mellem hydrogensulfid (H(2)S) og nitrogenmonoxid (NO). Det er gasser i blodet, som er med til at regulere kredsløbet. På engelsk kaldes de også for "gasotransmitters".

NO er interessant i relation til ME, fordi Olav Mella og Øystein Fluge i en præsentation har fremsat en hypotese om, at der kan være forstyrret NO syntese i endothelial celler og nedsat NO tilgængelighed. Endothelial celler er det lag celler, der dækker indersiden af blodkarrene.

Relationen mellem POTS og NO er undersøgt i flere studier, og jeg har ikke umiddelbart kunne finde en klar konklusion på sammenhængen.

Forhøjede værdier af H(2)S er sat i forbindelse med både ME og POTS. En artikel oplyser, at plasmaniveauet for børn med POTS var (100.9±2.1 μmol/L) og for den raske kontrolgruppe var det (82.6±6.5 μmol/L), hvilket er en signifikant forskel. Jeg ved ikke, hvorfor det er forhøjet. Er det en del af sygdomsmekanismen? Eller sørger kroppen for at opregulere H(2)S for at afhjælpe sygdommen? Men jeg tænker, at hvis noget afviger fra det normale, så var værd at undersøge det nærmere for at finde ud, hvorfor H(2)S er dysreguleret.

En nærmere kig på litteraturen afslører, at reguleringen af H(2)S og NO interagerer, og det er meget svært at måle H(2)S præcist, så artikler med måling af H(2)S skal fortolkes med forsigtighed. Ligesom forskellige målemetoder gør, at man ikke umiddelbart kan sammenligne forskellige forsøg.

Jeg fandt en artikel,
Plasma free H2S levels are elevated in patients with cardiovascular disease
hvor man havde lagt stor vægt på måleteknik og havde målt både H(2)S og NO hos en større patientgruppe med hjerte-kar sygdomme (studiet har ikke noget at gøre med ME eller POTS).

Men jeg finder artiklen interessant, fordi den tager nogle problemstillinger op, som også kan være relevante for ME og POTS, f.eks at der er ikke klinisk tilgængelig viden om den biokemiske sammenhæng mellem NO and H(2)S. Og det gør det jo unægtelig noget mere besværligt at være ME eller POTS patient, når man ikke kan få målt og fortolket parametre, som er under mistanke for at være dysregulerede. Og forskningen ikke endnu ikke forstår de her sammenhænge i gasotransmittere til bunds.

I artiklens forsøg målte man  plasma‐fri H(2)S og total NO på patienter med

• lidelser i kranspulsåren, (coronary artery disease alone, CAD)
• perifere kredsløbsforstyrrelser, (peripheral arterial disease alone, PAD)
• enhver karsygdom, (any vascular disease)  
• en rask kontrolgruppe (no vascular disease)

Og her er så de spændende resultater!

	No Vasc Disease, n=53	Any Vasc Disease, n=140	CAD Alone, n=66	PAD Alone, n=13
Plasma free H2S, nmol/L	368.53±20.87	441.04±15.40 (P =0.010)	443.89±21.67 (P =0.020)	514.48±62.05 (P =0.007)
Total NO levels, nmol/L	64.71±1.12	64.71±1.07 (P =0.997)	61.56±1.09 (P =0.743)	38.86±1.20 (P =0.034)

Table 3 fra artiklen: Plasma‐Free H2S and Total NO Levels in Vascular Disease

Konklusionen på hele forsøget (som jeg stærkt vil anbefale, at man læser i sin helhed) er, at resultaterne rapporteret i denne undersøgelse viser, at plasma-fri H(2)S niveauer er signifikant forhøjet i vaskulær sygdom og identificere en ny negativ korrelation med NO biotilgængelighed hos patienter med perifer arteriel sygdom.

Hvad med at foretage dette forsøg med 

• ME patienter
• POTS patienter
• ME/POTS patienter
• en rask kontrolgruppe

???

Update 15. juni 2014: Problems with measurement of H2S: Controversies and Conundrums in Hydrogen Sulfide Biology

Forslag til at læse mere om emnet:

Hydrogen sulfide downregulates the aortic l-arginine/nitric oxide pathway in rats

Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation

Regulation of Heart Function by Endogenous Gaseous Mediators—Crosstalk Between Nitric Oxide and Hydrogen Sulfide

Hydrogen sulfide, ME/CFS, POTS and TRPA1

Dysregulation of hydrogen sulfide, H(2)S, has been connected to ME/CFS in a hypothesis by Marian Lemle: Hypothesis: Chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism.

And De Meirleir has created a hydrogen sulfide test for ME/CFS. Read more about it here Originator of H2S Theory Speaks and here ATP, Hydrogen Sulfide, Natural Killer Cells and the Heart.

Perhaps it is time to take a look at hydrogen sulfide and ME/CFS again, and POTS!

This study
Plasma hydrogen sulfide in differential diagnosis between vasovagal syncope and postural orthostatic tachycardia syndrome in children
showed, that plasma levels of H(2)S were significantly higher in children with vasovagal syncope (VVS) (95.3±3.8 μmol/L) and POTS (100.9±2.1 μmol/L) than in children in the control group (82.6±6.5 μmol/L). Compared with the VVS group, the POTS group had plasma levels of H(2)S that were significantly increased.

If we combine the hypothesis that elevated H(2)S is part of ME/CFS/POTS and the hypothesis that N-methyl-D-aspartate receptor is sensitized in ME, this article becomes very interesting:
Physiological role of hydrogen sulfide and polysulfide in the central nervous system:

• The researchers demonstrated that H(2)S is a neuromodulator that facilitates hippocampal long-term potentiation (LTP) by enhancing the activity of N-methyl-D-aspartate (NMDA) receptors.
• It also induces Ca2+ influx in the astrocytes by activating the transient receptor potential ankyrin-1 (TRPA1) channels.
• In addition, the article shows the recent findings that indicate that the H(2)S-derived polysulfides found in the brain activate TRPA1 channels more potently than parental H(2)S.

The observations from the study suggest that polysulfides derived from H(2)S activate TRPA1 channels to induce Ca2+ influx in astrocytes. Activated astrocytes, in turn, release D-serine to the synapse to enhance the activity of NMDA receptors.

Can we expand the old hypothesis: Dysregulated H(2)S is involved in excessive activation of TRPA1 and NMDA receptor in ME/CFS and POTS?

Endothelial and mithocondrial dysfunction is also suspected to be part of ME/CFS. H(2)S is a potent inhibitor of mitochondrial respiration, and H(2)S is involved in the NOS pathway.

Update 15. juni 2014: Problems with measurement of H2S: Controversies and Conundrums in Hydrogen Sulfide Biology

Further reading:

TRP blogposts - an overview

Hydrogen sulfide and translational medicine

Actions and interactions of nitric oxide, carbon monoxide and hydrogen sulphide in the cardiovascular system and in inflammation — a tale of three gases!

The anti-thrombotic effect of hydrogen sulfide is partly mediated by an upregulation of nitric oxide synthases

H2S Protects Against Pressure Overload Induced Heart Failure via Upregulation of Endothelial Nitric Oxide Synthase (eNOS)

High concentrations of hydrogen sulphide elevate the expression of a series of pro-inflammatory genes in fibroblast-like synoviocytes derived from rheumatoid and osteoarthritis patients

Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide

TRP channels: sensors and transducers of gasotransmitter signals

H2S and its role in redox signaling

ME, MCS, TRPA1 og glutathion

TRPA1 er en receptor, som bl.a. findes i luftvejene og i celler i hjernen. TRPA1 indgår i mange sammenhænge, f.eks. bliver den aktiveret af kemikalier i forbindelse med advarsel/oprydning i kroppen. Forskellige kemiske forbindelser, f.eks. røg, fungerer som agonist til receptoren. Dvs de kemiske forbindelser aktiverer eller ”tænder” for receptoren.

Her har jeg oversat en passage fra denne artikel:
Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control

”For ethvert given kemikalie vil TRPA1 agonist aktivitet afhænge af den reversible eller irreversible karakter af de kemiske dannede bindinger og på agonist membran permeabilitet. Da de fleste TRPA1 agonister kan reagere med thioler, vil cellulære og ekstracellulære reduceret glutathion-niveauer påvirker rækkevidde og styrken af ​​inhalerede luftvejs irritanter. Når glutathion er opbrugt, enten som følge af sygdom eller ved længere eksponeringer, kan TRPA1 reagere langt stærkere. Med hvert åndedrag er mere reaktiv agonist leveret, hvilket fører til en stigning i kovalente ændringer og øget TRPA1 aktivitet. Denne kumulative effekt kan resultere i en robust TRPA1-induceret irritation selv ved lave sub-akutte eksponering niveaurt, for eksempel i perioder med øget fotokemisk smog, eller ved lavt niveau af indendørs luftforurening. Når de først er irriversibelt ændret, kan kanaler forblive aktiv i længere tid, selv når irriterende stimulus er fjernet.”

På godt dansk: Når vi indånder kemiske forbindelser, som er giftige for os, vil TRPA1 blive aktiveret, og der er brug for et stof, glutathion, til at rydde op. Når kroppen ikke kan følge med i dannelse af glutathion, så er vi lidt på den.

Det gælder så for alle mennesker, men hvad med mennesker med ME og MCS?

Det viser sig, at ME patienter mangler glutathion i hjernen, og at en del MCS patienter har ringere evne til "at rydde op med glutathion".

Det var da en pudsig sammenhæng mellem ME, MCS, TRPA1 og glutathion – sammen med alle de andre pudsige sammenhænge, som man kan læse om på min blog.

Nu er det her kun ”en lille bid” af en større biokemisk sammenhæng ( i en forenklet forklaring), men hvis man begyndte at kæde tingene sammen, kunne man måske løse gåden om ME/POTS/MCS/smerter, og hvordan det hele hang sammen.

TRPA1 som sensor for ilt – kan det have betydning for ME?

Jeg har rejst spørgsmålet om en dysregulering af receptoren TRPA1 er del af ætiologien bag ME. Og i min sidste blogpost gættede jeg på mulige mekanismer.

Der er endnu en god grund til at mistænke TRPA1 for at være en medspiller i ME. Post exertional malaise (PEM) og iltoptagelse i ME er kerneområder, der undersøges og diskuteres i sygdommen. Og TRPA1 kan også agere som ilt sensor og advarer om for meget og for lidt ilt (hyperoxia og hypoxia).

Peter Zygmont har skrevet en fremragende lille artikel om emnet, Channels: A TR(i)P in the air

Ikke alene gennemgås det, hvordan TRPA1 aktiveres både af hyperoxia og hypoxia, men han nævner også receptorens relevans for bl. a. migræne, irritable bowel disease (IBS), blære hyperaktivitet og fibromyalgi.

Mange af de sygdomme, som jeg nævner på min blog og som jeg sætter i forbindelse med TRPA1, kaldes i Danmark også for funktionelle lidelser. Det kan undre mig, at i et land som Danmark, hvor der anvendes to-cifrede millionbeløb på forskning i funktionelle lidelser, at jeg slet ikke kan finde noget om TRPA1.

Hvorfor indgår TRPA1 receptoren i så mange sammenhænge – og indgår den i ME?

Jeg har i tidligere blogposts angivet receptoren TRPA1, som en mulig indgående (dysreguleret) faktor i både POTS, MCS, smerter mm. Nu er TRPA1 bare en lille brik i et større biokemisk puslespil, hvor mange andre faktorer indgår. For at forstå hvordan en enkelt receptor kan være så mangfoldig, er man nødt til at forstå, hvad der påvirker den. Førend TRPA1 bliver aktiveret, kan der være indtruffet en række af biokemiske reaktioner.

Lad os kigge på et eksempel på, hvordan fornemmelsen af kløe opstår rent biokemisk. Her er TRPA1 også involveret. Så hvilken kæde af reaktioner fører til, at TRPA1 receptoren aktiveres og giver et signal?

I artiklen The Epithelial Cell-Derived Atopic Dermatitis Cytokine TSLP Activates Neurons to Induce Itch findes en figur, der viser den biokemiske række af hændelser før TRPA1 aktiveres og sender besked op gennem rygraden til hjernen. (Klik ind og se figuren)

Som det fremgår af figuren er den en række af hændelser: PAR2 → ORAI1 → NFAT → TSLP → TSLP receptor → TRPA1.

Det er ikke af betydning i denne sammenhæng at forstå kæden af hændelser, men blot at forstå, at der ER en kæde af reaktioner.

Et andet eksempel er TRPA1s medvirken til smerte hypersensitivtet.

Klik ind på denne figur Model Depicting Functional Interactions between Bradykinin Receptors, TRPA1 and TRPV1.

Her ses rækken af biokemiske reaktioner (interaktioner) : Bradykinin receptoren påvirker TRPV1 receptoren, som igen påvirker TRPA1 receptoren.

Nu er det, at man skal tænke videre. Hvis TRPA1 også er involveret i ME, så kan TRPA1 måske i sig være dysreguleret eller den kan interagere med en receptor, der er dysreguleret.

Her er det værd at bemærke, at TRP receptorer ofte interagerer med receptorer, der kaldes G protein koblede receptorer

og

G protein koblede receptorer er ofte mål for autoimmune angreb.

Her kunne man måske tænke sig, at HVIS ME havde en autoimmun ætiologi, og HVIS dette var rettet mod en G protein koblet receptor, så kunne det MÅSKE forstyrre TRPA1.

Det kan naturligvis også være en hel anden mekanisme, - måske en mekansime, hvor der bliver ophobet en metabolit, som forstyrrer TRPA1.

TRPA1 and pain

An exciting new study about TRPA1 and pain:

Differential methylation of the TRPA1 promoter in pain sensitivity

References in relation to the paper:

Pain sensitivity may be influenced by lifestyle and environment

Derfor oplever enæggede tvillinger smerte forskelligt

Derfor føler eneggede tvillinger smerte forskjellig


..og lidt mere om TRPA1:

URMENNESKER GRÆD OGSÅ NÅR DE SKAR LØG

A role for TRPs in ME/CFS/POTS/MCS/pain/endothelial dysfunction...?

TRP blogposts - an overview

Exercise followed by pain and exhaustion - is it ME?

Exercise, fasting and cold temperatures as triggers for pain episodes followed by exhaustion and deep sleep. The period of pain is accompanied by breathing difficulties, tachycardia and sweating. Is it Myalgic encephalomyelitis?

No, it is Gain-of-Function Mutation in TRPA1.

A point mutation in the S4 transmembrane segment of TRPA1, a key sensor for environmental
irritants, causes Familial Episodic Pain Syndrome. The mutant channel showed a normal pharmacological profile but altered biophysical properties, with a 5-fold increase in inward current on activation at normal resting potentials.

Check out the fine paper and video that explains the discovery:

A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome

More about TRPA1:

A role for TRPs in ME/CFS/POTS/MCS/pain/endothelial dysfunction...?

TRP blogposts - an overview

TRP blogposts - an overview

A role for TRPs in ME/CFS/POTS/MCS/pain/endothelial dysfunction...?

TRPA1, LPS and the possible connection to ME symptoms

TRPA1 and migraine - ME and migraine

Excessive activation of TRPA1 and TRPV1 by ROS may induce central sensitization – does it concern ME? 

TRPA1 og Multiple Chemical Sensitivity

A small peculiarity - ME, "ciguatoxin-look-alike" and TRPA1

Caveolae, eNOS and TRPA1?

Once again: TRPA1! Is activation of TRPA1 involved in ME?

Kan mRNA for TRPA1 benyttes som biomarkør for MCS?

Puslespilsbrikkerne: LPS, TLR4, TRPA1 og ME!?!

Vedvarende aktivering af TRPA1 og aflastning?

Variation i sensoriske reaktioner, TRP og stress

TRPA1, muskelaktivitet og påvirkning af det autonome nervesystem

ME, slow gastric emptying, serotonin and TRPA1

TRPA1, Hypoxia and ME?

Mitochondrial dysfunction - influence on TRPA1

Exercise and...TRPA1 and TRPV1

ME, neuropathy, TRPA1

TRPA1 involvement in autonomic dysfunction in ME?

TRPA1/TRPV4/PAR in inflammation/pain

Transient Receptor Potential in Multiple Chemical Sensitivity

TRP Ion Channels

A role for TRPs in ME/CFS/POTS/MCS/pain/endothelial dysfunction...?

TRPs are part of the biochemistry in health and disease.

A role for TRPs in ME/CFS/POTS/MCS/pain/endothelial dysfunction... ? Can some of the symptoms be explained, if we understand the TRPs?

TRP Ion Channels – especially TRPA1 references:

Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) [1]

Postural Orthostatic Tachycardia Syndrome (POTS) and vascular function [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9], [10], [11]

Multiple Chemical Sensitivity (MCS), asthma and airways [12] , [13] , [14] , [15] , [16] , [17], [18] , [19] , [20] , [21], [22] , [23]

Irritable Bowel Syndrome (IBS) and gastrointestinal tract [24], [25] , [26] , [27] , [28] , [29] , [30] , [31], [32] , [33]

Reflux [34] , [35]

Pain – inflammation – central sensitization - neuropathy [36], [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46], [47] , [48] , [49] , [50], [51], [52], [53] , [54] , [55], [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64], [65]

LPS – bacterial endotoxin [66]

Endothelial function/dysfunction [67], [68] , [69] , [70] , [71] ,[72] , [73]

Vascular function [74] , [75] , [76] , [77] , [78] , [79] ,[80] , [81] , [82]

Regulation af cerebral blood flow [83] ,[84] , [85]

Migraine [86], [87] , [88] , [89] , [90]

Exercise [91] , [92] , [93] , [94] , [95]

Stress [96] , [97] , [98]

Hypoxia, sensors of oxygen [99] , [100] , [101] , [102] , [103] ,[104]

Mitochondria, redox, ROS, RNS [105] , [106] , [107] , [108], [109] , [110] , [111]

Glial cells[112]

Dorsal root ganglion [113] , [114]

Vagus nerve [115]

Spinal Cord Injury (SCI) [116]

Bladder pain syndrome/ bladder dysfunction [117], [118], [119] , [120] , [121] , [122] , [123]

Rosacea [124]

Analgesia [125], [126], [127] , [128] , [129] , [130]

TRP in disease [131], [132]

TRP in sensory transduction and cellular signaling [133], [134] , [135]

TRP projects [136] , [137] ,

TRP patent applications [138] , [139] , [140], [141] , [142]

Treatment [143] , [144]

Inhibition of TRPA1 [145]

References:

[1] Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes.

[2] Evidence for the pathophysiological relevance of TRPA1 receptors in the cardiovascular system in vivo

[3] TRPA1 channels in the vasculature

[4] Transient receptor potential channels and vascular function

[5] Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow

[6] Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels

[7] TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation

[8] TRPA1 is involved in mediating vasodilation. TRPA1 can also influence changes in blood pressure of possible relevance to autonomic system reflexes and potentially to vasovagal/neurocardiogenic syncope disorders

[9] Involvement of TRPA1 receptors in meningeal blood flow induced by formation of nitroxyl (NO-/HNO)

[10] Redox Regulation of Endothelial Canonical Transient Receptor Potential Channels

[11] TRPA1 channels play a critical role in cold-induced vasodilatation

[12] Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control

[13] Activation of Transient Receptor Potential Ankyrin-1 (TRPA1) in Lung Cells by Wood Smoke Particulate Material

[14] Pre-clinical studies in cough research: Role of Transient Receptor Potential (TRP) channels

[15] Epithelial Cell TRPV1-Mediated Airway Sensitivity as a Mechanism for Respiratory Symptoms Associated with Gulf War Illness

[16] Transient Receptor Potential Channels Encode Volatile Chemicals Sensed by Rat Trigeminal Ganglion Neurons

[17] TRPA1 detects environmental chemicals and induces avoidance behavior and arousal from sleep

[18] Crucial Role of Transient Receptor Potential Ankyrin 1 and Mast Cells in Induction of Nonallergic Airway Hyperreactivity in Mice

[19] Transient receptor potential channels and occupational exposure

[20] Functional expression of the transient receptor potential channel TRPA1, a sensor for toxic lung inhalants, in pulmonary epithelial cells

[21] Pre-clinical studies in cough research: role of Transient Receptor Potential (TRP) channels

[22] A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

[23] Multiple types of sensory neurons respond to irritating volatile organic compounds (VOCs): calcium fluorimetry of trigeminal ganglion neurons

[24] Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain

[25] Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain.

[26] QGP-1 cells release 5-HT via TRPA1 activation; a model of human enterochromaffin cells

[27] TRPA1 agonists delay gastric emptying in rats through serotonergic pathways

[28] TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells

[29] Psychological Co-morbidity in Functional Gastrointestinal Disorders: Epidemiology, Mechanisms and Management

[30] Sensory neuro-immune interactions differ between irritable bowel syndrome subtypes

[31] Acute Uterine Irritation Provokes Colonic Motility via Transient Receptor Potential A1-dependent Spinal NR2B Phosphorylation in Rats

[32] Identification of enteroendocrine cells that express TRPA1 channels in the mouse intestine

[33] Effects of novel TRPA1 receptor agonist ASP7663 in models of drug-induced constipation and visceral pain

[34] Airway Reflux, Cough and Respiratory Disease

[35] Inflammation and Oxidative Stress in Gastroesophageal Reflux Disease

[36] Two to tango: GPCR oligomers and GPCR-TRP channel interactions in nociception.

[37] Role of Oxidative Stress and Ca(2+) Signaling on Molecular Pathways of Neuropathic Pain in Diabetes: Focus on TRP Channels.

[38] TRPA1 Mediates Mechanical Sensitization in Nociceptors during Inflammation

[39] Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control

[40] Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) Coupling is Required for Sustained Inflammatory Signaling

[41] Chemokines as Pain Mediators and Modulators

[42] Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy

[43] The dynamic TRPA1 channel: a suitable pharmacological pain target?

[44] Sustained TRPA1 activation in vivo

[45] Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels

[46] TRPA1: A Transducer and Amplifier of Pain and Inflammation

[47] Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling

[48] Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels

[49] Acrolein involvement in sensory and behavioral hypersensitivity following spinal cord injury in the rat

[50] Hydrogen sulfide-induced mechanical hyperalgesia and allodynia require activation of both Cav3.2 and TRPA1 channels in mice

[51] Sustained firing of TRPA1 elicited by reactive agonists

[52] Transient receptor potential A1 increase glutamate release on brain stem neurons

[53] TRPV1 and TRPA1 Mediate Peripheral Nitric Oxide-Induced Nociception in Mice

[54] Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors

[55] Sustained firing of TRPA1 elicited by reactive agonists

[56] Behavioral and Electrophysiological Study of Thermal and Mechanical Pain Modulation by TRP Channel Agonists

[57] Cortical spreading depression induces oxidative stress in the trigeminal nociceptive system

[58] Hypoxia-inducible Factor-1α (HIF1α) Switches on Transient Receptor Potential Ankyrin Repeat 1 (TRPA1) Gene Expression via a Hypoxia Response Element-like Motif to Modulate Cytokine Release

[59] Dynamic changes in the TRPA1 selectivity filter lead to progressive but reversible pore dilation

[60] NGF up-regulates TRPA1: implications for orofacial pain

[61] Differential methylation of the TRPA1 promoter in pain sensitivity

[62] Neurotrophins, endocannabinoids and thermo-transient receptor potential: a threesome in pain signalling

[63] Modulation of Transient Receptor Vanilloid 1 Activity by Transient Receptor Potential

Ankyrin 1

[64] TRP-channels as key integrators of lipid pathways in nociceptive neurons

[65] Methylglyoxal Evokes Pain by Stimulating TRPA1

[66] TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins

[67] TRP channels in endothelial function and dysfunction

[68] Expression and modulation of TRP channels in human microvascular endothelial cells

[69] Regulation and Function of TRPM7 in Human Endothelial Cells: TRPM7 as a Potential Novel Regulator of Endothelial Function

[70] Endothelium-dependent cerebral artery dilation mediated by transient receptor potential and Ca2+-activated K+ channels

[71] TRP channel Ca2+ sparklets: fundamental signals underlying endothelium-dependent hyperpolarization

[72] Model for TRPC5-mediated feedback of Ca2+ and NO signaling in endothelial cells and attenuation of Ca2+ entry through TRPC6 by NO in smooth muscle cells

[73] Cooperative Interaction of trp Melastatin Channel Transient Receptor Potential (TRPM2) With Its Splice Variant TRPM2 Short Variant Is Essential for Endothelial Cell Apoptosis

[74] Transient receptor potential channels and vascular function

[75] TRPA1 channels in the vasculature

[76] TRPV channels and vascular function

[77] TRP channels in vascular endothelial cells

[78] Evidence for the pathophysiological relevance of TRPA1 receptors in the cardiovascular system in vivo

[79] TRP channel and cardiovascular disease

[80] Transient Receptor Potential Channels in Cardiovascular Function and Disease

[81] Emerging concepts for the role of TRP channels in the cardiovascular system

[82] The NO/ONOO-cycle as the central cause of heart failure

[83] Endogenously-Generated Lipid Peroxidation Products Dilate Rat Cerebral Arteries by Activating TRPA1 Channels in the Endothelium

[84] TRANSIENT RECEPTOR POTENTIAL (TRP) CHANNELS, VASCULARTONE AND AUTOREGULATION OF CEREBRAL BLOOD FLOW

[85] Proposed Signaling Pathway for TRPA1-Mediated Vasodilation of Cerebral Arteries

[86] TRPA1 and other TRP channels in migraine

[87] Activation of TRPA1 on dural afferents: a potential mechanism of headache pain

[88] Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel

[89] Cortical spreading depression induces oxidative stress in the trigeminal nociceptive system

[90] The TRPA1 Channel in Migraine Mechanism and Treatment

[91] Transient receptor potentials (TRPs) and anaphylaxis

[92] Muscle Afferent Receptors Engaged in Augmented Sympathetic Responsiveness in Peripheral Artery Disease

[93] Transient receptor potential A1 channel contributes to activation of the muscle reflex

[94] Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects

[95] Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls

[96] TRPV1 is a stress response protein in the central nervous system.

[97] Importance of TRP channels in pain: implications for stress

[98] Table 1. Cross-talk between several stress-related factors and TRP channels

[99] TRPA1 underlies a sensing mechanism for O2

[100] Reference: Channels: A TR(i)P in the air

[101] Reference: TRP channels: sensors and transducers of gasotransmitter signals

[102] Hypoxia-inducible factor-1α (HIF1α) switches on transient receptor potential ankyrin repeat 1 (TRPA1) gene expression via a hypoxia response element-like motif to modulate cytokine release

[103] Hypersensitivity of lung vagal C fibers induced by acute intermittent hypoxia in rats: role of reactive oxygen species and TRPA1

[104] TRP channels as sensors of oxygen availability

[105] Sensory Nerve Terminal Mitochondrial Dysfunction Activates Airway Sensory Nerves Via Transient Receptor Potential (TRP) Channels

[106] Role of Reactive Oxygen Species and Redox in Regulating the Function of Transient Receptor Potential Channels

[107] Sensory Nerve Terminal Mitochondrial Dysfunction Activates Airway Sensory Nerves Via Transient Receptor Potential (TRP) Channels

[108] Redox Regulation of Transient Receptor Potential Channels

[109] Transnitrosylation Directs TRPA1 Selectivity in N-Nitrosamine Activators

[110] Emerging roles of TRPA1 in sensation of oxidative stress and its implications in defense anddanger

[111] Transient Receptor Potential A1 Is a Sensory Receptor for Multiple Products of Oxidative Stress

[112] Pathophysiological roles of transient receptor potential channels in glial cells.

[113] Systematic and quantitative mRNA expression analysis of TRP channel genes at the single trigeminal and dorsal root ganglion level in mouse

[114] Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels

[115] TRPV1, TRPA1, and CB1 in the isolated vagus nerve--axonal chemosensitivity and control of neuropeptide release

[116] Acrolein involvement in sensory and behavioral hypersensitivity following spinal cord injury in the rat

[117] Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: Implication for the pathogenesis of interstitial cystitis/bladder pain syndrome.

[118] Mechanisms of Disease: involvement of the urothelium in bladder dysfunction

[119] THE ROLE OF TRPA1 CHANNELS IN ACTIVATION OF SINGLE UNIT MECHANOSENSITIVE BLADDER AFFERENT ACTIVITIES IN THE RAT

[120] TRPA1 receptor modulation attenuates bladder overactivity induced by spinal cord injury

[121] Distribution and function of the hydrogen sulfide-sensitive TRPA1 ion channel in rat urinary bladder

[122] Antagonism of the transient receptor potential ankyrin 1 (TRPA1) attenuates hyperalgesia andurinary bladder overactivity in cyclophosphamide-induced haemorrhagic cystitis

[123] Transient receptor potential channels in bladder function

[124] Neurovascular Aspects of Skin Neurogenic Inflammation

[125] TRPA1 as an Analgesic Target

[126] Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors

[127] Targeting TRP channels for pain relief

[128] TRP channels and analgesia

[129] Transient Receptor Potential Ankyrin 1 (TRPA1) Channel as Emerging Target for Novel Analgesics and Anti-Inflammatory Agents

[130] SuperPain—a resource on pain-relieving compounds targeting ion channels

[131] Transient receptor potential cation channels in disease.

[132] DYSREGULATED MRNAS MAY ALSO EXPLAIN COMMON CO-MORBIDITIES OF CFS

[133] TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades.

[134] Chapter 11 TRPA1 : A Sensory Channel of Many Talents

[135] The molecular basis for species-specific activation of human TRPA1 by protons involves poorly conserved residues within transmembrane domains 5 and 6

[136] ROLE OF TRP CHANNELS IN ENVIRONMENTAL IRRITANT-INDUCED HEADACHE DESCRIPTION

[137] POST-EXERCISE ION CHANNEL GENE EXPRESSION BIOMARKERS IN CFS

[138] NOVEL TRPA1 ANTAGONISTS

[139] Treatment of Respiratory Disorders using TRPA1 Antagonists

[140] PHARMACEUTICAL COMPOSITION COMPRISING A TRPA1 ANTAGONIST AND AN ANTICHOLINERGIC AGENT

[141] Heterocyclic amides as modulators of TRPA1

[142] Compounds useful for treating disorders related to TRPA1

[143] Modulation of TRP channels by resveratrol and other stilbenoids

[144] USE OF TRPA1 RECEPTOR ANTAGONISTS FOR TREATING DISEASES ASSOCIATED WITH BACTERIAL INFECTIONS

[145] Superpain database