Tag Archive for: TRPV1 antagonist

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Capsaicin, resiniferatoxin and botulinum toxin-A – a trip down memory lane

Over 20 years ago, I went to work at Queen Square, the Mecca of Neurology, as Medical Research Council fellow to Prof. Clare Fowler, an international expert in the neurogenic bladder. She has now retired leaving a lasting legacy, which features in this edition of the BJUI.

I clearly remember my first meeting with Vijay Ramani (now Consultant Urologist in Manchester) and Dirk De Ridder (Associate Editor, BJUI), which led to a collaborative paper on the effects of capsaicin in refractory neurogenic detrusor overactivity (NDO) [1]. While we were busy studying suburothelial nerves in NDO, with many hours of computerised image analysis, a seminal paper describing the ‘capsaicin receptor’ appeared in Nature [2]. This was my first encounter with transient receptor potential (TRP) channels. They continue to excite urologists and neurologists alike as potential therapeutic targets in overactive and painful bladders [3].

Just like semisynthetic capsaicin, derived from chillies, which acted through TRP receptors, TRPV1 antagonists are effective but have numerous side-effects including hyperthermia. No surprises here But there are other subtypes, such as TRPV4 and TRPM8, which are generating a lot of interest in the field of drug discovery.

Life, of course, moved on. Capsaicin never received a license for NDO and was followed by resiniferatoxin (RTX), which also made a rapid exit as it adhered to the plastic bags that it was dispensed in as a solution. Botulinum toxin-A turned out to be the game changer [4]. After extensive trials and safety studies, it has changed the lives of many millions with incontinence secondary to DO, who have failed most other first-line treatments. It has a licence for clinical use and the science behind its mechanism of action has led to many fascinating discoveries.

So, are TRP inhibitors the next big thing in functional urology? After 20 years of fundamental research, they certainly have the potential. As with most eureka moments in translational research, only time will tell.

 

References

 

1 De Ridder D, Chandiramani V, Dasgupta P, Van Poppel H, Baert LFowler CJ. Intravesical capsaicin as a treatment for refractory detrusor hyperreexia: a dual center study with long-term followup. J Urol 1997; 158: 208792

 

2 Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D. A capsaicin- receptor homologue with a high threshold for noxious heat. Nature 1999; 398: 43641

 

 

 

Prokar Dasgupta @prokarurol
Editor-in-Chief, BJUI 

 

Article of the Week: Co-administration of TRPV4 and TRPV1 antagonists potentiate the effect of each drug

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Prof. Francisco Cruz, discussing his paper. 

If you only have time to read one article this week, it should be this one.

Co-administration of transient receptor potential vanilloid 4 (TRPV4) and TRPV1 antagonists potentiate the effect of each drug in a rat model of cystitis

Ana Charrua†‡§, Célia D. Cruz‡§, Dick Jansen¶ , Boy Rozenberg¶ , John Heesakkers¶ and Francisco Cruz*†§

*Department of Urology, S. João Hospital, †Department of Renal, Urologic and Infectious Disease, ‡Department of Experimental Biology, Faculty of Medicine of the University of Porto, §IBMC – Instituto de Biologia Molecular e Celular da Universidade do Porto, Porto, Portugal, and ¶Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Read the full article
OBJECTIVE

To investigate transient receptor potential vanilloid 4 (TRPV4) expression in bladder afferents and study the effect of TRPV4 and TRPV1 antagonists, alone and in combination, in bladder hyperactivity and pain induced by cystitis.

MATERIALS AND METHODS

TRPV4 expression in bladder afferents was analysed by immunohistochemistry in L6 dorsal root ganglia (DRG), labelled by fluorogold injected in the urinary bladder. TRPV4 and TRPV1 co-expression was also investigated in L6 DRG neurones of control rats and in rats with lipopolysaccharide (LPS)-induced cystitis. The effect of TRPV4 antagonist RN1734 and TRPV1 antagonist SB366791 on bladder hyperactivity and pain induced by cystitis was assessed by cystometry and visceral pain behaviour tests, respectively.

RESULTS

TRPV4 is expressed in sensory neurones that innervate the urinary bladder. TRPV4-positive bladder afferents represent a different population than the TRPV1-expressing bladder afferents, as their co-localisation was minimal in control and inflamed rats. While low doses of RN1734 and SB366791 (176.7 ng/kg and 143.9 ng/kg, respectively) had no effect on bladder activity, the co-administration of the two totally reversed bladder hyperactivity induced by LPS. In these same doses, the antagonists partially reversed bladder pain behaviour induced by cystitis.

CONCLUSIONS

TRPV4 and TRPV1 are present in different bladder afferent populations. The synergistic activity of antagonists for these receptors in very low doses may offer the opportunity to treat lower urinary tract symptoms while minimising the potential side-effects of each drug.

Read more articles of the week

Editorial: How much potential for Transient Receptor Potential channels in the bladder?

In this issue of the BJUI, Charrua et al. [1] report on the possible interaction of two members of the vanilloid subfamily of transient receptor potential (TRP) channels in the control of rat urinary bladder function, TRPV1 and TRPV4. TRP channels are a family of cation-selective channels with 28 known mammalian members. Six of them belong to the subfamily of vanilloid receptors (TRPV channels) and fall into four groups, TRPV1/TRPV2, TRPV3, TRPV4, and TRPV5/TRPV6. The physiological and pharmacological interest in these channels results largely from the finding that they can be activated by a plethora of physical and chemical stimuli; accordingly, they have been implicated in sensory function and pathophysiology of many organ systems [2]. A breakthrough in our understanding of such channels came with the reporting of TRPV1 and TRPV4 knock-out mice, which also exhibit a bladder phenotype; the role of TRP channels in lower urinary tract function has comprehensively been reviewed recently [3].

While the physiological regulation of TRPV1 by endogenous mediators is poorly understood, natural compounds such as capsaicin or resiniferatoxin are acute agonists of TRPV1 channels; however, over time, they desensitise the channel and hence act as inhibitors. These compounds have shown promise in the treatment of detrusor overactivity but also have problems attributed to their initial agonist effects [3]. TRPV4 are activated experimentally by hypotonicity induced cell swelling and several chemicals and more physiologically by moderate heat, stretch and shear stress, leading to the proposition that they may functions as a stretch sensor in the bladder. The inhibitory effects of TRPV1 agonists manifest only after prolonged exposure once desensitisation of their agonist effects occurs, and this initial agonistic phase is a source of undesirable effects. Therefore, a search is on for small molecules that have direct antagonist effects.

Charrua et al. [1] now report that two small molecule antagonists at TRPV1 and TRPV4, (SB355791 and RN1734, respectively) even in high doses did not affect bladder function in control rats. Intravesical installation of lipopolysaccharide is used to create an animal model of cystitis as it induces inflammation, detrusor overactivity and bladder pain. In this model, a high dose of the TRPV4 inhibitor reduced detrusor overactivity, whereas even the high dose of the TRPV1 inhibitor did not; however, a combination of ineffective doses of both inhibitors markedly decreased bladder reflex activity. On the other hand, each of the two drugs caused partial analgesia, but their combination was not more effective than either drug alone. This indicates an interesting functional interaction between TRPV1 and TRPV4 channels, which is specific for the overactivity vs the pain response. Previously, the Cruz group reported that bladder overactivity induced by nerve growth factor depends on the presence of functionally active TRPV1 [4]. Taken together this work shines light on networks of multiple mediators and their receptors that cooperate in the regulation of bladder function but previously have mainly been viewed in isolation. Such work may also have therapeutic consequences. As target-saturating concentrations of ligands at any of these receptors may cause relevant adverse effects, targeting multiple such receptors in low doses may open an avenue for a multi-pronged approach, particularly in patients with bladder dysfunction difficult to control with present treatment options.

This multiple target, low-dose approach is a therapeutically fascinating idea, but finding the right combination of doses in such a setting is a nightmare for any drug development scientist. Moreover, much of the specific role of such targets in pathophysiology remains to be explored before the present findings can be translated into clinical treatments, and the Charrua et al. study [1] will also help such efforts in other ways. Some of the initial thinking on the function of TRP channels in the control of bladder and other functions has been based on localisation studies with TRP channel antibodies, which may have been flawed. Similar to many other receptor antibodies [5], several of those directed against TRPV1 channels also have been shown to lack target specificity [6], leading to misunderstandings about the location and function of such channels. The validation for other TRPV1 and TRPV4 antibodies presented by Charrua et al. [1] will allow more robust studies in this regard and help to develop more valid understanding of TRP channels in physiology, pathophysiology and as treatment targets.

Read the full article
Martin C. Michel

 

Department of Pharmacolog y , Johannes Gutenberg University, Mainz, Germany

 

References

 

 

 

3 Franken J, Uvin P, de Ridder D, Voets T. TRP channels in lower urinary tract dysfunction. Br J Pharmacol 2014; 171: 2537–51

 

4 Frias B, Charrua A, Avelino A, Michel MC, Cruz F, Cruz CD. Transient receptor potential vanilloid 1 mediates nerve growth factor-induced bladder hyperactivity and noxious input. BJU Int 2012; 110: E422–8

 

5 Michel MC, Wieland T, Tsujimoto G. How reliable arG-protein-coupled receptor antibodies? Naunyn Schmiedebergs Arch Pharmacol 2009; 377: 385–8

 

6 Everaerts W, Sepúlveda MR, Gevaert T, Roskams T, Nilius B, De Ridder D. Where is TRPV1 expressed in the bladder, do we see the real channel? Naunyn Schmiedebergs Arch Pharmacol 2009; 379: 421–5

 

Video: Co-administration of TRPV4 and TRPV1 antagonists

Co-administration of transient receptor potential vanilloid 4 (TRPV4) and TRPV1 antagonists potentiate the effect of each drug in a rat model of cystitis

Ana Charrua†‡§, Célia D. Cruz‡§, Dick Jansen¶ , Boy Rozenberg¶ , John Heesakkers¶ and Francisco Cruz*†§

*Department of Urology, S. João Hospital, †Department of Renal, Urologic and Infectious Disease, ‡Department of Experimental Biology, Faculty of Medicine of the University of Porto, §IBMC – Instituto de Biologia Molecular e Celular da Universidade do Porto, Porto, Portugal, and ¶Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Read the full article
OBJECTIVE

To investigate transient receptor potential vanilloid 4 (TRPV4) expression in bladder afferents and study the effect of TRPV4 and TRPV1 antagonists, alone and in combination, in bladder hyperactivity and pain induced by cystitis.

MATERIALS AND METHODS

TRPV4 expression in bladder afferents was analysed by immunohistochemistry in L6 dorsal root ganglia (DRG), labelled by fluorogold injected in the urinary bladder. TRPV4 and TRPV1 co-expression was also investigated in L6 DRG neurones of control rats and in rats with lipopolysaccharide (LPS)-induced cystitis. The effect of TRPV4 antagonist RN1734 and TRPV1 antagonist SB366791 on bladder hyperactivity and pain induced by cystitis was assessed by cystometry and visceral pain behaviour tests, respectively.

RESULTS

TRPV4 is expressed in sensory neurones that innervate the urinary bladder. TRPV4-positive bladder afferents represent a different population than the TRPV1-expressing bladder afferents, as their co-localisation was minimal in control and inflamed rats. While low doses of RN1734 and SB366791 (176.7 ng/kg and 143.9 ng/kg, respectively) had no effect on bladder activity, the co-administration of the two totally reversed bladder hyperactivity induced by LPS. In these same doses, the antagonists partially reversed bladder pain behaviour induced by cystitis.

CONCLUSIONS

TRPV4 and TRPV1 are present in different bladder afferent populations. The synergistic activity of antagonists for these receptors in very low doses may offer the opportunity to treat lower urinary tract symptoms while minimising the potential side-effects of each drug.

Read more articles of the week
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