Sympathetic neurotransmitter metabolism in Hirschsprung's disease

Tyrosine hydroxylase activity was measured in high speed supernatants obtained from full thickness segments of aganglionic and ganglionic colon of three children with Hirschsprung's disease. Tyrosine hydroxylase activity expressed as pmole DOPA/mg protein/min was 0.93 +/- 0.16 in ganglionic and 2.67 +/- 0.21 in aganglionic colon. Tyrosine hydroxylase activity in ganglionic colon rose to 2.29 +/- 0.11 following calcium stimulation (100 muM) but could not be further increased in aganglionic colon. Addition of norepinephrine (2 X 10(-4) M) to tissue homogenates inhibited tyrosine hydroxylase activity in ganglionic colon by 57 +/- 8% but only by 14 +/- 3% in aganglionic colon, suggesting that the enzyme present in aganglionic colon is insensitive to feedback inhibition by endogenous norepinephrine. The elevation of tyrosine hydroxylase activity in aganglionic colon and its insensitivity to calcium stimulation and norepinephrine inhibition is further evidence of sympathetic overactivity in the aganglionic colon and suggests a basic enzymatic abnormality in the pathogenesis of Hirschsprung's disease.