Inhibition of dopamine β-hydroxylase by fusaric acid (5-butylpicolinic acid) in vitro and in vivo

Abstract

Fusaric acid (5-butylpicolinic acid) was found to be a potent inhibitor of dopamine β-hydroxylase in vitro and in vivo. Fusaric acid inhibited the enzyme by 50 per cent at a concentration of 3 × 10 −8 M. Kinetic studies with purified dopamine β-hydroxylase showed that the inhibition by fusaric acid was of the uncompetitive type with the substrate and of the mixed type with a cofactor, ascorbic acid. Fusaric acid lowered endogenous levels of norepinephrine and epinephrine in brain, heart, spleen and adrenal glands. Maximum depletion of norepinephrine and epinephrine was observed between 3 and 6 hr after the administration of fusaric acid. Since dopamine β-hydroxylase activity in adrenal medulla was found to be inhibited in vivo after the administration of fusaric acid, the decrease in the catecholamine levels is attributed to the inhibition of norepinephrine synthesis at the dopamine β-hydroxylase stage.