The role of kinin B1 receptor and the effect of angiotensin I-converting enzyme inhibition on acute gout attacks in rodents.

Abstract

OBJECTIVE:

Verify the role of the kinin B1 receptors (B1R) and the effect of ACE inhibitors (ACEi) on acute gout induced by monosodium urate (MSU) crystals in rodents.

METHODS:

Painful (overt pain and allodynia) and inflammatory parameters (joint oedema, leukocyte trafficking, interleukin-1β levels) of acute gout attacks were assessed several hours after an intra-articular injection of MSU (1.25 or 0.5 mg/articulation) into the ankle of rats or mice, respectively. The role of B1R was investigated using pharmacological antagonism or gene deletion. Additionally, B1R immunoreactivity in ankle tissue and sensory neurons, kininase I activity and des-Arg(9)-bradykinin synovial levels were also measured. Similar tools were used to investigate the effects of ACEi on a low dose of MSU (0.0125 mg/articulation)-induced inflammation.

RESULTS:

Kinin B1R antagonism or gene deletion largely reduced all painful and inflammatory signs of gout. Furthermore, MSU increased B1R expression in articular tissues, the content of the B1 agonist des-Arg(9)-bradykinin and the activity of the B1 agonist-forming enzyme kininase I. A low dose of MSU crystals, which did not induce inflammation in control animals, caused signs of acute gout attacks in ACEi-treated animals that were B1R-dependent.

CONCLUSIONS:

Kinin B1R contributes to acute gouty attacks, including the ones facilitated by ACEi. Therefore, B1R is a potential therapeutic target for the treatment and prophylaxis of gout, especially in patients taking ACEi.

• Authors: Cássia R Silva, Sara M Oliveira, Carin Hoffmeister, Vinícius Funck, Gustavo P Guerra, Gabriela Trevisan, Raquel Tonello, Mateus F Rossato, João B Pesquero, Michael Bader, Mauro S Oliveira, Jason J McDougall, Juliano Ferreira
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 75 Issue 1 Pg. 260-8 (Jan 2016) ISSN: 1468-2060 [Electronic] England
• PMID: 25344431 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Chemical References

• 2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide
• Angiotensin-Converting Enzyme Inhibitors
• Bradykinin B1 Receptor Antagonists
• Dioxoles
• Receptor, Bradykinin B1
• Sulfonamides
• Uric Acid

Topics

• Acute Disease
• Angiotensin-Converting Enzyme Inhibitors (therapeutic use)
• Animals
• Bradykinin B1 Receptor Antagonists (therapeutic use)
• Dioxoles (therapeutic use)
• Edema (chemically induced, metabolism)
• Gout (chemically induced, drug therapy, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Pain (chemically induced, metabolism)
• Rats, Wistar
• Receptor, Bradykinin B1 (physiology)
• Sulfonamides (therapeutic use)
• Uric Acid