Substance P and neurokinin A metabolism by cultured human skeletal muscle myocytes and fibroblasts.
A recent study determined that cultured human skeletal muscle adult myoblasts, myotubes, and fibroblasts degraded angiotensins and kinins via neutral endopeptidase-24.11 (NEP-24.11: EC 3.4.24.11) and aminopeptidase N (APN: EC 3.4.11.2). Due to the possible importance of other peptides to skeletal muscle blood flow and function, the present study looked specifically at the metabolism of the neurokinins substance P (SP) and neurokinin A (NKA) by skeletal muscle peptidases. The results show that SP is degraded not only by NEP-24.11, but also sequentially by dipeptidyl(amino)peptidase IV (DAP IV: EC 3.4.14.5)/APN. NKA is unaffected by DAP IV but is metabolized by NEP-24.11 and APN. NEP-24.11 was inhibited by phosphoramidon (IC50 = 80 nM), thiorphan and ZINCOV, DAP IV by diprotin A (IC50 = 8 microM), and APN by amastatin (IC50 = 50 nM) and bestatin (IC50 = 100 microM). Skeletal muscle myocyte and fibroblast metabolism of SP and NKA may regulate local skeletal muscle vascular and extravascular functions including SP- and NKA-mediated nerve-induced vasodilation. Inhibition of both NEP-24.11 and DAP IV/APN may increase skeletal muscle blood flow and decrease peripheral vascular resistance via potentiation of local neurokinin levels.
Russell
J S
JS
Department of Physiology, Ohio State University, Columbus 43210, USA.
Chi
H
H
Lantry
L E
LE
Stephens
R E
RE
Ward
P E
PE
D000328:Adult; D001783:Blood Flow Velocity / Q000502:physiology; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D018482:Muscle, Skeletal / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D015260:Neprilysin / Q000378:metabolism; D015288:Neurokinin A / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism*; D014655:Vascular Resistance / Q000502:physiology
D013373:Substance P; D015288:Neurokinin A; D018819:Dipeptidyl Peptidase 4; D015260:Neprilysin