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

Bradley J Undem, Marian Kollarik

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)716-722
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume303
Issue number2
DOIs
StatePublished - Nov 1 2002

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Unmyelinated Nerve Fibers
Capsaicin
Action Potentials
Smooth Muscle
Guinea Pigs
iodoresiniferatoxin
vanilloid receptor subtype 1
Neurokinin A
Muscle Contraction
Trachea
Trypsin
Binding Sites

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Characterization of the vanilloid receptor 1 antagonist iodo-resiniferatoxin on the afferent and efferent function of vagal sensory C-fibers",
abstract = "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.",
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N2 - 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.

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.

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