RT Journal Article
SR Electronic
T1 Characterization of the Vanilloid Receptor 1 Antagonist Iodo-Resiniferatoxin on the Afferent and Efferent Function of Vagal Sensory C-Fibers
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 716
OP 722
DO 10.1124/jpet.102.039727
VO 303
IS 2
A1 Bradley J. Undem
A1 Marian Kollarik
YR 2002
UL http://jpet.aspetjournals.org/content/303/2/716.abstract
AB 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 pKB 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. The American Society for Pharmacology and Experimental Therapeutics