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 microM) had no VR1 agonist activity in either the afferent or efferent assays. I-RTX (30 nM-1 microM) 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 microM 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 microM I-RTX on capsaicin-evoked contractions compared with 0.3 microM I-RTX. Concentrations of I-RTX up to 1 microM 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 microM I-RTX. In both afferent and efferent studies I-RTX (30 nM-1 microM) 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.
Undem
Bradley J
BJ
Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA. bundem@jhmi.edu
Kollarik
Marian
M
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004594:Electrophysiology; D005110:Extracellular Space / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects*; D009475:Neurons, Afferent / Q000187:drug effects*; D009476:Neurons, Efferent / Q000187:drug effects*; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D050916:TRPV Cation Channels; D014630:Vagus Nerve / Q000166:cytology* / Q000187:drug effects
D004224:Diterpenes; D011955:Receptors, Drug; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C468130:iodoresiniferatoxin; D002211:Capsaicin