Suppression of myocardial protein degradation by the protease inhibitor bis[ethyl(2R,3R)-3-[(S)-methyl-1-[4-(2,3,4-tri-methoxy-phenyl-methyl) piperazine-1-ylcarbonyl]butyl-carbonyl]oxiran-2-carboxylat e]sulfate under hypoxia.
The synthetic protease inhibitor bis[ethyl(2R,3R)-3-[(S)-methyl-1-[4-(2,3,4-tri-methoxyphenyl-methyl) piperazine-1-ylcarbonyl]butyl-carbonyl]oxiran-2-carboxylate] sulfate (NCO-700) suppressed both activities of calcium-activated neutral protease and cathepsin B isolated from cardiac muscle, showing 50% inhibition at 46 and 0.8 mumol/l, respectively. A kinetics study using 14C-labelled NCO-700 suggested its incorporation into cultured myocardial cells, demonstrating the half-maximal saturation time at 17 min. Under both aerobic and hypoxic conditions, the reagent inhibited the peptide release from cultured myocardial cells dose-dependently. The amino acid release from heart slices of adult rabbit was also blocked by the drug under hypoxic and glucose-depleted condition. These data and the myocardial infarction size reducing action of NCO-700 might support the view that NCO-700 sensitive protease(s) - possibly, calcium-activated neutral protease and/or cathepsin B - is (are) working to induce an irreversible proteolysis in the process of myocardial cell degradation.
D000332:Aerobiosis; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002401:Cathepsin B; D002403:Cathepsins / Q000037:antagonists & inhibitors; D002417:Cattle; D002478:Cells, Cultured; D010450:Endopeptidases; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D015260:Neprilysin; D010100:Oxygen / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*
D000596:Amino Acids; D009124:Muscle Proteins; D010879:Piperazines; D011480:Protease Inhibitors; C036798:NCO 700; D002403:Cathepsins; D010450:Endopeptidases; D002401:Cathepsin B; D015260:Neprilysin; D010100:Oxygen