Investigating the potential role of <scp>TRPA</scp>1 in locomotion and cardiovascular control during hypertension

Bodkin, Jennifer V.; Thakore, Pratish; Aubdool, Aisah A.; Liang, Lijun; Fernandes, Elizabeth S.; Nandi, Manasi; Spina, Domenico; Clark, James E.; Aaronson, Philip I.; Shattock, Michael J.; Brain, Susan D.

doi:10.1002/prp2.52

Cited by 36 publications

(28 citation statements)

References 56 publications

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“…Moreover, both telemetry (simultaneous and nonsimultaneous recordings) and the tail-cuff reflected the expected hypertensive response that the pressor agent AngII is associated with. 27,44 Although the nonsimultaneous and tail-cuff readings were remarkably similar, the simultaneous readings remained significantly higher than tail-cuff readings. This difference was observed throughout the hypertensive protocol.…”

Section: Discussionmentioning

confidence: 88%

Tail‐Cuff Technique and Its Influence on Central Blood Pressure in the Mouse

Wilde

Aubdool

Thakore

et al. 2017

JAHA

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BackgroundReliable measurement of blood pressure in conscious mice is essential in cardiovascular research. Telemetry, the “gold‐standard” technique, is invasive and expensive and therefore tail‐cuff, a noninvasive alternative, is widely used. However, tail‐cuff requires handling and restraint during measurement, which may cause stress affecting blood pressure and undermining reliability of the results.Methods and ResultsC57Bl/6J mice were implanted with radio‐telemetry probes to investigate the effects of the steps of the tail‐cuff technique on central blood pressure, heart rate, and temperature. This included comparison of handling techniques, operator's sex, habituation, and influence of hypertension induced by angiotensin II. Direct comparison of measurements obtained by telemetry and tail‐cuff were made in the same mouse. The results revealed significant increases in central blood pressure, heart rate, and core body temperature from baseline following handling interventions without significant difference among the different handling technique, habituation, or sex of the investigator. Restraint induced the largest and sustained increase in cardiovascular parameters and temperature. The tail‐cuff readings significantly underestimated those from simultaneous telemetry recordings; however, “nonsimultaneous” telemetry, obtained in undisturbed mice, were similar to tail‐cuff readings obtained in undisturbed mice on the same day.ConclusionsThis study reveals that the tail‐cuff technique underestimates the core blood pressure changes that occur simultaneously during the restraint and measurement phases. However, the measurements between the 2 techniques are similar when tail‐cuff readings are compared with telemetry readings in the nondisturbed mice. The differences between the simultaneous recordings by the 2 techniques should be recognized by researchers.

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Section: Discussionmentioning

confidence: 88%

Tail‐Cuff Technique and Its Influence on Central Blood Pressure in the Mouse

Wilde

Aubdool

Thakore

et al. 2017

JAHA

Self Cite

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“…Because TRPA1 antagonists are not yet available for human use, we were not able to test the specificity of the response to CA for TRPA1 in humans. However, extensive preclinical experiments support this specificity and currently no evidence for species differences in CA sensitivity has been reported [12,32,33]. In line with other DBF models such as the capsaicin model, one can assume that several factors such as sex, age and body site can play a role in the response to CA.…”

Section: Figurementioning

confidence: 90%

Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

Buntinx

Chang

Amin

et al. 2016

Brit J Clinical Pharma

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AIMTo develop a non-invasive, safe and reproducible target-engagement biomarker for future TRPA1 antagonists in healthy volunteers. METHODSDose finding (n = 11): 3%, 10%, and 30% cinnamaldehyde (CA) and placebo (= vehicle) was topically applied on the right forearm. One-way ANOVA with post-hoc Bonferroni was used to compare between doses. Reproducibility: 10% CA doses were topically applied during one visit on both arms (n = 10) or during two visits (n = 23) separated by a washout period of 7 days. CA-induced dermal blood flow (DBF) was assessed by laser Doppler imaging (LDI) at baseline and at 10, 20, 30, 40 and 50 min post-CA. Paired t-test was used to compare between arms or visits. Concordance correlation coefficient (CCC) was calculated to assess reproducibility. Data are expressed as percent change from baseline (mean ± 95% CI). RESULTSAll three doses increased DBF compared to vehicle at all time-points, with the maximum response at 10-20 min post-CA. Dose response was found when comparing AUC 0-50min of 30% CA (51 364 ± 8475%*min) with 10% CA (32 239 ± 8034%*min, P = 0.03) and 3% CA (30 226 ± 11 958%*min, P = 0.015). 10% CA was chosen as an effective and safe dose. DBF response to 10% CA was found to be reproducible between arms (AUC 0-50min , CCC = 0.91) and visits (AUC 0-50min , CCC = 0.83). Based on sample size calculations, this model allows a change in CA-induced DBF of 30-50% to be detected between two independent groups of maximum 10-15 subjects with 80% power. CONCLUSIONSEvaluation of CA-induced changes in DBF offers a safe, non-invasive and reproducible target-engagement biomarker in vivo in humans to evaluate TRPA1 antagonists. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Cinnamaldehyde, the main component of cinnamon, activates the TRPA1 receptor and induces vasodilatation when applied on the human skin.• TRPA1, a non-selective cation channel, is expressed in small diameter nociceptors and involved in persistent to chronic painful states such as inflammation, neuropathic pain and migraine.• TRPA1 is an emerging target for treating these and other neurogenic inflammatory conditions. WHAT THIS STUDY ADDS• Cinnamaldehyde 10% topical solution is tolerable and safe to use in healthy volunteers.• Cinnamaldehyde 10% applied on the human skin induces a robust increase in dermal blood flow which can be measured with laser Doppler imaging and is reproducible over time and between arms. • The cinnamaldehyde model can be used in future early clinical development studies with TRPA1 antagonists as a target engagement biomarker to guide dose selections for efficacy studies. Tables of Links

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“…This raises a question if targeting TRPA1 could have unintended/unrecognized adverse effects on physiological functions or on known protective functions such as sensing environmental irritants. TRPA1 KO mice are recently reported to show physical hyperactivity [57]. Since several TRPA1 antagonists are at different stages of evaluation including chemical synthesis, preclinical studies and clinical trials, their long term safety in patients is likely to be addressed soon.…”

Section: Trpa1 Antagonists: Any Safety Concerns?mentioning

confidence: 99%

Blocking TRPA1 in Respiratory Disorders: Does It Hold a Promise?

2016

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Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel is expressed abundantly on the C fibers that innervate almost entire respiratory tract starting from oral cavity and oropharynx, conducting airways in the trachea, bronchi, terminal bronchioles, respiratory bronchioles and upto alveolar ducts and alveoli. Functional presence of TRPA1 on non-neuronal cells got recognized recently. TRPA1 plays a well-recognized role of “chemosensor”, detecting presence of exogenous irritants and endogenous pro-inflammatory mediators that are implicated in airway inflammation and sensory symptoms like chronic cough, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cystic fibrosis. TRPA1 can remain activated chronically due to elevated levels and continued presence of such endogenous ligands and pro-inflammatory mediators. Several selective TRPA1 antagonists have been tested in animal models of respiratory disease and their performance is very promising. Although there is no TRPA1 antagonist in advanced clinical trials or approved on market yet to treat respiratory diseases, however, limited but promising evidences available so far indicate likelihood that targeting TRPA1 may present a new therapy in treatment of respiratory diseases in near future. This review will focus on in vitro, animal and human evidences that strengthen the proposed role of TRPA1 in modulation of specific airway sensory responses and also on preclinical and clinical progress of selected TRPA1 antagonists.

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Investigating the potential role of TRPA1 in locomotion and cardiovascular control during hypertension

Cited by 36 publications

References 56 publications

Tail‐Cuff Technique and Its Influence on Central Blood Pressure in the Mouse

Tail‐Cuff Technique and Its Influence on Central Blood Pressure in the Mouse

Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

Blocking TRPA1 in Respiratory Disorders: Does It Hold a Promise?

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