Recombinant neutral endopeptidase attenuates substance P-induced plasma extravasation in the guinea pig skin.
To determine whether exogenously administered neutral endopeptidase (NEP; enkephalinase, EC 3.4.24.11) inhibits the substance P-induced increase in vascular permeability in the skin, we examined the effects of recombinant human NEP on plasma extravasation induced by intradermal injection of substance P in guinea pig skin. Injection of substance P (2.5 X 10(-8) M) induced significant plasma extravasation in the skin (53 +/- 4 mm2 of Evans blue extravasation; mean +/- 1 SEM). In vitro incubation of substance P with recombinant human NEP prior to injection prevented the substance P-induced plasma extravasation in the skin in a dose-dependent fashion. Intradermal preinjection of recombinant human NEP partially inhibited plasma extravasation induced by subsequent injection of substance P (52 +/- 9% of the control without NEP). The H1 and H2 histamine antagonists pyrilamine and cimetidine, and a muscarinic antagonist, atropine, had no effects on substance P-induced responses. Two products of substance P degradation by NEP containing the carboxy-terminal portion, substance P7-11 and substance P8-11, were also without effect. These findings suggest that recombinant human NEP can attenuate substance P-induced increases in vascular permeability in guinea pig skin and, therefore, may be useful in treating dermatologic disorders in which abnormal responses to substance P or other neuropeptides cleaved by NEP may occur.
Rubinstein
I
I
Cardiovascular Research Institute, University of California, San Francisco.
Iwamoto
I
I
Ueki
I F
IF
Borson
D B
DB
Nadel
J A
JA
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D006168:Guinea Pigs; D007271:Injections, Intradermal; D015260:Neprilysin / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012867:Skin / Q000098:blood supply*; D013373:Substance P / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D011994:Recombinant Proteins; D013373:Substance P; D015260:Neprilysin