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.
Footnotes
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This study was funded by The National Institutes of Health (Bethesda, MD).
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DOI: 10.1124/jpet.102.039727
- Abbreviations:
- VR1
- vanilloid receptor 1
- I-RTX
- iodo-resiniferatoxin
- KBS
- Krebs bicarbonate solution
- NKA
- neurokinin A
- NK1
- neurokinin 1 receptor
- NK2
- neurokinin 2 receptor
- SR48968
- (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide
- SR140333
- (S)-1-[2-[3-(3,4-dichlorophenyl)-1-(3-isoproproxyphenylacetyl)piperidin-3-yl]ethyl]-4-phenyl-1-azoniabicyclo[2.2.2.]octane chloride
- Received June 4, 2002.
- Accepted July 10, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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