Characterization of the Vanilloid Receptor 1 Antagonist Iodo-Resiniferatoxin on the Afferent and Efferent Function of Vagal Sensory C-Fibers

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 303; no. 2; pp. 716 - 722
• Main Authors: Undem, Bradley J, Kollarik, Marian
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.11.2002
• Subjects: Action Potentials - drug effects; Animals; Binding, Competitive - drug effects; Capsaicin - pharmacology; Diterpenes - pharmacology; Dose-Response Relationship, Drug; Electric Stimulation; Electrophysiology; Extracellular Space - drug effects; Guinea Pigs; In Vitro Techniques; Male; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - innervation; Nerve Fibers, Unmyelinated - drug effects; Neurons, Afferent - drug effects; Neurons, Efferent - drug effects; Receptors, Drug - antagonists & inhibitors; TRPV Cation Channels; Vagus Nerve - cytology; Vagus Nerve - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.039727

The effect of iodo-resiniferatoxin (I-RTX) on efferent function (tachykinergic contractions of airway smooth muscle) and afferent function (action potential discharge) of vagal C-fibers mediated by vanilloid receptor 1 (VR1) activation was studied in an isolated guinea pig airway preparation. I-RTX (1 μM) had no VR1 agonist activity in either the afferent or efferent assays. I-RTX (30 nM–1 μM) shifted the resiniferatoxin and capsaicin concentration-response curves for neurokinin-mediated contractions rightward but did not inhibit the maximum response. The p K B value calculated from 0.3 μM I-RTX against resiniferatoxin and capsaicin was 7.3 ± 0.2 and 6.8 ± 0.2, respectively, showing 10 to 30 times higher potency compared with capsazepine. The slope of Schild plot from the resiniferatoxin efferent studies deviated from unity (∼0.6), suggesting complex interactions at VR1 binding site(s). This notion was further supported by lack of additional inhibitory effect of 1 μM I-RTX on capsaicin-evoked contractions compared with 0.3 μM I-RTX. Concentrations of I-RTX up to 1 μM had no effect on trypsin-induced neurokinin-mediated contractions, nor neurokinin A-induced contractions of guinea pig trachea. However, nonselective effects on airway smooth muscle contractions were noted with 10 μM I-RTX. In both afferent and efferent studies I-RTX (30 nM–1 μM) caused a substantial delay of the response to capsaicin. This led to an apparent increase in potency in experiments where the agonist was applied transiently, with insufficient time to reach equilibrium. I-RTX inhibited contractions induced by anandamide and action potential discharge induced by low pH, showing that the I-RTX-antagonism of VR1 does not strictly depend on the vanilloid nature of the agonist.