Neutral endopeptidase modulates substance P-induced vasodilation in vivo.
The purpose of this study was to investigate whether neutral endopeptidase (NEP; EC 3.4.24.11) modulates substance P-induced vasodilation in the oral mucosa in vivo. Using intravital microscopy, we measured the diameter of second-order arterioles (44-70 microns) in the hamster cheek pouch during suffusion of capsaicin and substance P. We found that capsaicin (0.1 and 10.0 nM) induced significant concentration-dependent vasodilations (13 +/- 4 and 39 +/- 7% increase from baseline, respectively; P < 0.05) that were significantly potentiated by phosphoramidon (10.0 nM), a selective NEP inhibitor (35 +/- 15 and 61 +/- 12% increase from baseline, respectively; P < 0.05). Substance P (0.1 and 10.0 nM) also induced significant concentration-dependent vasodilations (7 +/- 3 and 25 +/- 8% increase from baseline, respectively; P < 0.05) that were mediated by the COOH-terminal of the molecule. Substance P-induced responses were significantly potentiated by phosphoramidon (34 +/- 9 and 53 +/- 10% increase from baseline, respectively; P < 0.05) and thiorphan (10.0 microM), a selective NEP inhibitor (44 +/- 11 and 53 +/- 10% increase from baseline, respectively; P < 0.05). Substance P-(1-9) had no significant effects on arteriolar diameter. Suffusion of captopril, leupeptin, Bestatin, and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid together had no significant effects on substance P-induced vasodilation. Phosphoramidon did not potentiate nitroglycerin-induced vasodilation. These data indicate that NEP modulates substance P-induced vasodilation in the hamster cheek pouch in vivo. We suggest that any decrease in tissue NEP activity may amplify neurogenic vasodilation in the oral mucosa.
Gao
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Department of Medicine, University of Illinois at Chicago, USA.
Rubinstein
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D000818:Animals; D001160:Arterioles / Q000033:anatomy & histology / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D006224:Cricetinae; D006020:Glycopeptides / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D009061:Mouth Mucosa / Q000098:blood supply; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000502:physiology*; D005996:Nitroglycerin / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D006020:Glycopeptides; D011480:Protease Inhibitors; D013373:Substance P; D015260:Neprilysin; D005996:Nitroglycerin; D002211:Capsaicin; C008890:phosphoramidon