Hydrazonopropionic Acids, a New Class of Hypoglycemic Substances 4. Hypoglycemic Effect of 2-(3-Methyl-Cinnamylhydrazono)-Propionate in the Rat and Guinea Pig

Summary

The hydrazone-compound 2-(3-methyl-cinnamylhydrazono)-propionate (MCHP) significantly lowered the blood glucose concentration in fasted guinea pigs and rats. A significant decrease of blood glucose levels was observed in fasted guinea pigs already after an intraperitoneal injection of 20.5 μmol/kg MCHP, while much higher doses (about 1000 μmol/kg) were necessary to produce a hypoglycemic effect in the fasted rat. After oral administration MCHP (82.0 μmol/kg) significantly decreased the blood glucose concentration in guinea pigs. Furthermore MCHP caused a dose-dependent increase of plasma free fatty acid concentrations in guinea pigs and rats. In addition, MCHP decreased the concentrations of blood ketone bodies, plasma cholesterol and intrahepatic acetyl-coenzyme A in the guinea pig. All of these findings appear to be due to a reduced fatty acid utilization in the presence of MCHP resulting presumably in an intramitochondrial deficiency of acetyl-CoA. At hypoglycemic effective doses the intramitochondrial and cytoplasmatic redox ratios as well as the hepatic ATP/ADP ratio were not influenced by MCHP in fasted guinea pigs. Even at large doses (123 μmol/kg) MCHP decreased the activity of monoamino oxidase in guinea pigs only by less than 15%. Furthermore MCHP showed under our experimental conditions no relevant influence on the activity of various liver enzymes in plasma, the plasma concentration of creatinine, the plasma triglyceride-glycerol level and on the intrahepatic triglyceride-glycerol concentration of fasted guinea pigs. It is concluded that MCHP meets basic requirements for a potential oral antidiabetic agent.

Key-Words:

Hypoglycemic Compound - 2-(3-Methyl-Cinnamylhydrazono)-Propionate - Guinea Pigs - Redox Ratios - Ketone Bodies - Free Fatty Acids - Acetyl-CoA - Monoamino Oxidase