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

Abstract

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.

MATERIAL 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.

• Authors: Ana Charrua, Célia D Cruz, Dick Jansen, Boy Rozenberg, John Heesakkers, Francisco Cruz
• Journal: BJU international (BJU Int) Vol. 115 Issue 3 Pg. 452-60 (Mar 2015) ISSN: 1464-410X [Electronic] England
• PMID: 25041193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. BJU International © 2014 BJU International.

Chemical References

• Anilides
• Cinnamates
• N-(3-methoxyphenyl)-4-chlorocinnamanilide
• RN 1734
• Sulfonamides
• TRPV Cation Channels

Topics

• Anilides (pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Cinnamates (pharmacology)
• Cystitis (drug therapy, metabolism)
• Disease Models, Animal
• Drug Discovery
• Female
• Ganglia, Spinal (chemistry)
• Mice
• Mice, Knockout
• Molecular Sequence Data
• Pain Measurement
• Rats
• Rats, Wistar
• Sulfonamides (pharmacology)
• TRPV Cation Channels (antagonists & inhibitors, metabolism)
• Urinary Bladder (drug effects)