Abstract
Early angiogenesis is a key step in the transition from acute to persistent inflammation. The nervous system has long been known to play a role in inflammation, in part through the release of substance P from peripheral nerve terminals (neurogenic inflammation). Application of substance P can stimulate vessel growth in a variety of angiogenesis assays, although it was previously not known whether endogenous substance P released from sensory nerves could modulate angiogenesis. We hypothesized that endogenous substance P can initiate angiogenesis during acute neurogenic inflammation. Here we show that 10 nmol of substance P can stimulate angiogenesis within the rat knee synovium, as shown by increased endothelial cell proliferation index [PCNA index, 19% (95% confidence interval (CI), 17 to 20%)] compared with saline injected knees [6% (95% CI, 4% to 8%), p < 0.05]. Moreover, this was prevented by coadministration of an antagonist of the neurokinin-1 (NK1) subtype of neurokinin receptor SR140333 (nolpitantium), 1 μmol [8% (95% CI, 5% to 11%)]. Capsaicin 0.5%, which stimulates release of endogenous substance P from sensory nerves, was also found to enhance synovial angiogenesis, [PCNA index 17% (95% CI, 14% to 19%)] compared with saline injected control knees [2% (95% CI, 1% to 3%), p < 0.05], and this also was inhibited by 1 μmol of SR140333 [11% (95% CI, 8 to 16%)]. Inhibition of capsaicin-enhanced angiogenesis was incomplete, and this may indicate a contribution of other neuropeptides, in addition to substance P-NK1 receptor interactions, in capsaicin-enhanced angiogenesis. NK1 receptor antagonists could have therapeutic potential in conditions where neurogenic angiogenesis contributes to disease.
Footnotes
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This work was supported by Arthritis Research Campaign Project Grant W584 (Sanofi-Synthelabo, France) for the neurokinin-1 and -2 antagonists. H.S. is supported by the Marie Curie Fellowship.
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DOI: 10.1124/jpet.103.050013.
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ABBREVIATIONS: NK1, neurokinin-1; PCNA, proliferating cell nuclear antigen; DAPI, 4′-6′-diamidino-2-phenylindole hydrochloride; CI, confidence interval; SR140333, nolpitantium; SR140333,1-[2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidi-n-3-yl]ethyl]-4-phenyl-1-azoniabicyclo[2.2.2]octane, chloride; SR144190, (R)-3-(1-[2-(4-benzoyl-2-(3,4-difluorophenyl)-morpholin-2-yl)-ethyl]-4-phenylpiperidin-4-yl)-1-dimethylurea; SR160603, R enantiomer of SR140333; RP-67580 {2-[1-imino-2-(2-methoxyphenyl)ethyl-7,7-diphenyl-4-perhydroisoindolone(3aR,7aR).
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↵1 Current address: AstraZeneca R&D, Charnwood, Loughborough, LE11 5RH, UK.
- Received February 4, 2003.
- Accepted March 14, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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