Effects of brocresine (NSD-1055) and cycloheximide on amino acid decarboxylase activities in gastric mucosa of normal and vagally denervated rats.

Abstract

1. Histidine decarboxylase activity of rat stomach fluctuates depending upon the functional state of the stomach. This varying enzyme activity poses special problems in assessing the effectiveness of enzyme inhibitors. After vagal denervation gastric histidine decarboxylase is markedly activated and remains at a high, stable level, which is unaffected by the functional state of the stomach. Thus it appears that vagally denervated rats are well suited for studies on histidine decarboxylase inhibitors.2. In vivo, brocresine (NSD-1055) was found to be a more effective inhibitor of gastric DOPA decarboxylase than of gastric histidine decarboxylase. With the fairly high dose given (200 mg/kg) the inhibition of histidine decarboxylase was at most 75-85% and quite short-lasting. The DOPA decarboxylase activity, which was not affected by vagal denervation, was inhibited more than 95% by brocresine; this inhibition was longer-lasting.3. Cycloheximide, which probably lowers gastric histidine decarboxylase activity by inhibiting enzyme synthesis, was maximally effective at a dose level as low as 1 mg/kg. Gastric DOPA decarboxylase was not inhibited by cycloheximide. Vagotomized rats and control rats responded similarly.4. Combined treatment of vagally denervated rats with brocresine and cycloheximide resulted in a rapid and persistent reduction of the histidine decarboxylase activity. It is concluded that the failure of brocresine alone to induce a lasting inhibition of histidine decarboxylase is due to continuous, rapid synthesis of new enzyme.5. The calculated half-life of gastric histidine decarboxylase was 75 min in vagally denervated rats and 45 min in normal fasted rats. The results suggest that the increased enzyme activity after vagal denervation is caused by an increased rate of enzyme synthesis.