Characterization of the vanilloid receptor 1 antagonist iodo-resiniferatoxin on the afferent and efferent function of vagal sensory C-fibers

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 muM) had no VR1 agonist activity in either the afferent or efferent assays. I-RTX (30 nM-1 muM) shifted the resiniferatoxin and capsaicin concentration-response curves for neurokinin-mediated contractions rightward but did not inhibit the maximum response. The pK(B) value calculated from 0.3 muM 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 (similar to0.6), suggesting complex interactions at VR1 binding site(s). This notion was further supported by lack of additional inhibitory effect of 1 muM I-RTX on capsaicin-evoked contractions compared with 0.3 muM I-RTX. Concentrations of I-RTX up to 1 muM 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 muM I-RTX. In both afferent and efferent studies I-RTX (30 nM-1 muM) 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.