PEDIATRICS Vol. 93 No. 4 April 1994, pp. 647-651
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Nitric Oxide Synthase Is Deficient in the Aganglionic Colon of Patients With Hirschsprung's Disease

John F. Bealer MD1, Eileen S. Natuzzi MD1, Cori Buscher 1, Alan W. Flake MD1, N. Scott Adzick MD1, Michael R. Harrison MD1, and Philip C. Ursell MD2

1 The Fetal Treatment Center, Departments of Surgery
2 Pathology, University of California-San Francisco

Objectives. The cause of Hirschsprung's disease is unknown but defects in nonadrenergic, noncholinergic innervation could prevent relaxation of aganglionic colon in patients with this disease. Nonadrenergic, noncholinergic nerves induce relaxation by using nitric oxide synthase to produce the smooth muscle relaxant nitric oxide (NO). In this study we asked whether aganglionic colon in patients with Hirschsprung's disease is deficient in NO synthase-containing nerves.

Methodology. Using the tetrazolium blue dye method of demonstrating nicotinamide adenine dinucleotide phosphate-diaphorase enzymes, we examined eight colon specimens (four aganglionic and four ganglionic) from patients with Hirschsprung's disease for the presence of NO synthase. We further quantified NO synthase enzyme activity in these eight specimens by using the [3H]arginine-to-[3H]citrulline conversion assay.

Results. The nicotinamide adenine dinucleotide phosphate-diaphorase staining showed that aganglionic colon contained less NO synthase than ganglionic colon. This NO synthase deficiency was located primarily in the nerves of the circular muscle layer of the colon. In addition, there was a striking difference in the NO synthase enzyme activity between aganglionic and ganglionic colon as measured by the [3H]arginine-to-[3H]citrulline conversion assay. Total NO synthase activity, as measured by this assay, was found to be less in aganglionic than in ganglionic colon. When the total activity was divided into its four known isoforms, aganglionic colon was noted to be striking deficient in the isoform derived primarily from nerves.

Conclusion. We conclude that aganglionic colon is deficient in NO synthase-containing nerves. This deficiency could prevent smooth muscle relaxation in the aganglionic colon of patients with Hirschsprung's disease.

Submitted on June 11, 1993
Accepted on September 13, 1993




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