SUBSTANCE-P AND NEUROKININ-A METABOLISM BY CULTURED HUMAN SKELETAL-MUSCLE MYOCYTES AND FIBROBLASTS

A recent study determined that cultured human skeletal muscle adult my oblasts, myotubes, and fibroblasts degraded angiotensins and kinins vi a neutral endopeptidase-24.11 (NEP-24.11: EC 3.4.24.11) and aminopepti dase N (APN; EC 3.4.11.2). Due to the possible importance of other pep tides to skeletal muscle blood Bow and function, the present study loo ked specifically at the metabolism of the neurokinins substance P (SP) and neurokinin A (NKA) by skeletal muscle peptidases. The results sho w 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 unaff ected 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 mu M), and APN by amastatin (IC50 = 50 nM) and bestatin (IC50 = 100 mu M). Skeletal muscle myocyte and fibroblas t metabolism of SP and NKA may regulate local skeletal muscle Vascular and extravascular functions including SP- and NKA-mediated nerve-indu ced Vasodilation. Inhibition of both NEP-24.11 and DAP IV/APN may incr ease skeletal muscle blood flow and decrease peripheral Vascular resis tance via potentiation of local neurokinin levels. Copyright (C) 1996 Elsevier Science Inc.