Nitro-oleic acid targets transient receptor potential (TRP) channels in capsaicin sensitive afferent nerves of rat urinary bladder

• Published in: Experimental neurology Vol. 232; no. 1; pp. 90 - 99
• Main Authors: Artim, D.E., Bazely, F., Daugherty, S.L., Sculptoreanu, A., Koronowski, K.B., Schopfer, F.J., Woodcock, S.R., Freeman, B.A., de Groat, W.C.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.11.2011; Elsevier
• Subjects: Afferent nerve; Animals; Biological and medical sciences; Capsaicin - pharmacology; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Injuries of the nervous system and the skull. Diseases due to physical agents; Medical sciences; Neurokinin; Neurology; Nitro-fatty acid; Oleic Acid - pharmacology; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells - drug effects; Sensory System Agents - pharmacology; Transient receptor potential acrylin receptor 1; Transient receptor potential vanilloid receptor 1; Traumas. Diseases due to physical agents; TRPV Cation Channels - agonists; TRPV Cation Channels - antagonists & inhibitors; Urinary Bladder - drug effects; Urinary Bladder - innervation; Urinary Bladder - physiology; Transient receptor potential vanilloid receptor 1; Transient receptor potential acrylin receptor 1; Neurokinin; Nitro-fatty acid; Afferent nerve; Nervous system diseases; Rat; Capsaicin; Rodentia; Transients; Vertebrata; Mammalia; TRP ion channel; Urinary system; Urinary bladder; Oleic acid; Animal; Vanilloid receptor; Transient receptor potential vanilloid; receptor 1; Biological receptor
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2011.08.007

Nitro-oleic acid (9- and 10-nitro-octadeca-9-enoic acid, OA-NO 2) is an electrophilic fatty acid nitroalkene derivative that modulates gene transcription and protein function via post-translational protein modification. Nitro-fatty acids are generated from unsaturated fatty acids by oxidative inflammatory reactions and acidic conditions in the presence of nitric oxide or nitrite. Nitroalkenes react with nucleophiles such as cysteine and histidine in a variety of susceptible proteins including transient receptor potential (TRP) channels in sensory neurons of the dorsal root and nodose ganglia. The present study revealed that OA-NO 2 activates TRP channels on afferent nerve terminals in the urinary bladder and thereby increases bladder activity. The TRPV1 agonist capsaicin (CAPS, 1 μM) and the TRPA1 agonist allyl isothiocyanate (AITC, 30 μM), elicited excitatory effects in bladder strips, increasing basal tone and amplitude of phasic bladder contractions (PBC). OA-NO 2 mimicked these effects in a concentration-dependent manner (1 μM–33 μM). The TRPA1 antagonist HC3-030031 (HC3, 30 μM) and the TRPV1 antagonist diaryl piperazine analog (DPA, 1 μM), reduced the effect of OA-NO 2 on phasic contraction amplitude and baseline tone. However, the non-selective TRP channel blocker, ruthenium red (30 μM) was a more effective inhibitor, reducing the effects of OA-NO 2 on basal tone by 75% and the effects on phasic amplitude by 85%. In bladder strips from CAPS-treated rats, the effect of OA-NO 2 on phasic contraction amplitude was reduced by 65% and the effect on basal tone was reduced by 60%. Pretreatment of bladder strips with a combination of neurokinin receptor antagonists (NK1 selective antagonist, CP 96345; NK2 selective antagonist, MEN 10,376; NK3 selective antagonist, SB 234,375, 1 μM each) reduced the effect of OA-NO 2 on basal tone, but not phasic contraction amplitude. These results indicate that nitroalkene fatty acid derivatives can activate TRP channels on CAPS-sensitive afferent nerve terminals, leading to increased bladder contractile activity. Nitrated fatty acids produced endogenously by the combination of fatty acids and oxides of nitrogen released from the urothelium and/or afferent nerves may play a role in modulating bladder activity. ► Nitro-oleic acid increases phasic contractions and baseline tone in rat bladder strips. ► Nitro-oleic acid targets TRP channels on capsaicin-sensitive afferent nerves. ► Nitro-oleic acid effects involve release of neuropeptides. ► The effects require activation of L-type calcium channels. ► Nitro-fatty acids can modulate bladder function.