Vol. 303, Issue 2, 716-722, November 2002

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

Bradley J. Undem and Marian Kollarik

Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland

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 pK_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.