WHAT THIS STUDY ADDS:

• Abnormal levels of ADMA (a nitric oxide synthase inhibitor) and DDAH I (which controls ADMA expression) may help explain why patients with pulmonary hypertension often respond to nitric oxide administration.

CHARLOTTESVILLE, VA—Administration of nitric oxide (NO) produces short-term improvement in patients with pulmonary hypertension, but why this treatment is effective has been unclear because multiple studies have demonstrated increased pulmonary expression of NO synthase in such patients. However, new research sheds light on this paradox.

Using a rat model, researchers at the University of Virginia Health System in Charlottesville found that hypoxia-induced pulmonary hypertension is associated with increased concentrations of the NO synthase inhibitor asymmetric dimethylarginine (ADMA) and decreased levels of dimethylarginine dimethylaminohydrolase I (DDAH I), which controls the expression of ADMA.[1]

These enzymatic abnormalities suggest that in patients with pulmonary hypertension, NO synthesis decreases despite increased NO synthase expression. Furthermore, altering levels of these enzymes could treat or prevent pulmonary hypertension.

MURINE MODELING

Forty-eight rats were exposed to either normal oxygen levels (control group) or 10% oxygen (hypoxia group) for one week. After seven days, all rats in the hypoxia group developed pulmonary hypertension; none of the other rats did.

Expression of endothelial NO synthase increased 1.9-fold in the hypoxia group. In contrast, expression of DDAH I protein decreased significantly, although it was strongly expressed in the control group. In fact, the lungs of the rats in the hypoxia group expressed 37% less DDAH I protein than did the lungs of the rats in the control group. Pulmonary DDAH enzyme activity was also significantly reduced in the hypoxia group. DDAH II was not detectable in either group.

Pulmonary NO production decreased 22.4% in the hypoxia group, and pulmonary ADMA content increased 2.3-fold. There was a significant negative correlation between pulmonary DDAH activity and pulmonary ADMA in both groups.

LUNG NITRIC OXIDE IS DECREASED

In pulmonary hypertension, the decrease in NO synthesis is accompanied by increased pulmonary concentrations of ADMA. The authors hypothesized that decreased pulmonary NO production may contribute to pulmonary hypertension by reducing NO-dependent vasodilation.

An infusion of L-arginine, an endogenous NO synthase substrate, has been shown in both animal and human studies to increase plasma NO concentrations and to decrease right ventricular hypertrophy. These studies all indicated that pulmonary hypertension was a result of a chronic decrease in NO availability.

“DDAH I may play an important role in the pathogenesis of pulmonary hypertension because of the resultant increased concentrations of ADMA and thus inhibition of pulmonary NO synthase activity,” the authors wrote. DDAH I may therefore represent “a novel therapeutic target ” for pulmonary hypertension. Gene transfer of DDAH to the pulmonary vasculature might reduce ADMA concentrations and thereby treat or prevent pulmonary hypertension.

—Gale Jurasek

Reference
1. Millatt LJ, Whitley GS, Li D, et al. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation. 2003;108:1493-1498.

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