title: Inhibition of neutral endopeptidase (NEP) facilitates neurogenic inflammation.
abstract: Neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) are involved in neuropeptide degradation and may modulate neurogenic inflammation. We therefore explored the effect of specific blockers of NEP and ACE on the intensity of neurogenic inflammation. We investigated eight subjects on three occasions. Two pairs of microdialysis fibers equipped with intraluminal wires were inserted intracutaneously into the volar forearms and electrical stimuli were delivered via the intraluminal electrodes. The microdialysis fibers were perfused either with normal saline, phosphoramidon (NEP inhibitor), or captopril (ACE inhibitor). CGRP release was assessed in the microdialysis eluate via a specific EIA and by evaluating the extent and intensity of the neurogenic flare via a laser Doppler imager. The area of hyperalgesia and allodynia was assessed during electrical stimulation. Inhibition of NEP with phosphoramidon increased flare intensity (P < 0.002) and size (P < 0.01), while blocking ACE had no effect on neurogenic vasodilation. CGRP release could be measured in microdialysis samples after phosphoramidon perfusion only (P < 0.03), not in samples with captopril or saline perfusion. No effect on the areas of hyperalgesia and allodynia could be detected. Our findings suggest that NEP but not ACE is most important for CGRP degradation in human skin. This may be of particular importance for the understanding of pain disorders like migraine or complex regional pain syndrome.
authors.affiliation: Department of Neurology, Johannes Gutenberg-University, Langenbeckstr. 1, 55101 Mainz, Germany. kraemer@neurologie.klinik.uni-mainz.de
authors.forename: H H
authors.initials: HH
authors.lastname: Krämer
authors.forename: K
authors.initials: K
authors.lastname: Schmidt
authors.forename: S
authors.initials: S
authors.lastname: Leis
authors.forename: M
authors.initials: M
authors.lastname: Schmelz
authors.forename: C
authors.initials: C
authors.lastname: Sommer
authors.forename: F
authors.initials: F
authors.lastname: Birklein
mesh_terms: D000328:Adult; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002216:Captopril / Q000009:adverse effects* / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology*; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology; D007124:Immunoenzyme Techniques / Q000379:methods; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D017551:Microdialysis / Q000379:methods; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D036421:Nerve Fibers, Unmyelinated / Q000528:radiation effects; D020078:Neurogenic Inflammation / Q000139:chemically induced*; D007703:Peptidyl-Dipeptidase A / Q000494:pharmacology; D012867:Skin / Q000294:innervation / Q000503:physiopathology; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects / Q000528:radiation effects
chemical_list: D004791:Enzyme Inhibitors; D006020:Glycopeptides; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D015740:Calcitonin Gene-Related Peptide; C008890:phosphoramidon