To the Editor: We thank Drs Srilatha, Meng, and Adaikan for their letter “Hydrogen sulfide: in the aftermath of argininosuccinate lyase and nitric oxide deficiency,”1 regarding therapeutic strategies aimed at treating the nitric oxide (NO) deficiency in subjects with argininosuccinate lyase deficiency (ASLD). The authors suggest the interesting possibility of providing H2S donors as a therapeutic modality for ASLD instead of NO donors and discuss the potential drawbacks with NO donor therapy.

We agree that long-term NO supplementation for the treatment of conditions such as hypertension in the general population have met with limited success.2 However, the systemic deficiency of NO in ASLD makes NO supplementation an attractive treatment option for this condition. Whereas the usage of organic nitrates is compromised by tachyphylaxis, nitrite, as an active metabolite of nitrate, can be used therapeutically to bypass enzymatic tolerance.3 We have investigated the utility of NOS-independent NO supplementation in a mouse model and in human subjects with ASLD.4 Human subjects with ASLD have decreased NO production and impaired NOS-dependent vascular relaxation that responds to NO donors.4 Mice that are hypomorphic for ASLD have global NO deficiency and multiorgan involvement including systemic hypertension.4 Treatment of these mice with the NO donor sodium nitrite led to improved weight gain, increased survival, and correction of hypertension. To determine whether the systemic phenotype, in this case hypertension, is independent of the hepatic urea cycle disorder, we treated ASLD mice with liver-directed helper-dependent adenoviral gene therapy.5 Not surprisingly, despite correction of the metabolic defect in hepatic ureagenesis, mice continued to have hypertension.5 In ASLD mice treated with gene therapy, aortic ring studies continued to show impaired vascular relaxation because of the tissue autonomous NO deficiency. The short-term infusion of sodium nitrite indeed resulted in correction of hypertension. We translated these findings in a proof-of-principle study by testing the potential efficacy of organic nitrates and sodium nitrite in treating long-term resistant hypertension in a subject with ASLD.5 In this ASLD subject, hypertension was diagnosed at 5 years of age and for a period of over 10 years, the blood pressure of the subject was significantly elevated despite therapy with four different classes of first-line antihypertensive medications (beta blocker, calcium channel blocker, diuretic, and angiotensin converting enzyme inhibitor). In contrast, NO supplementation with organic nitrates in this subject resulted in rapid and sustained normalization of blood pressure and allowed for withdrawal of all other antihypertensive medications for 9 months. However, because of the concern that tachyphylaxis could lead to a resistance to organic nitrates, we substituted therapy with a custom formulation containing sodium nitrite. The subject now continues to be normotensive on nitrite monotherapy for an additional period of over 12 months. These data suggest that long-term complications in ASLD, such as hypertension, specifically result from the tissue-specific lack of NO, and that NO donors can provide long-term therapeutic benefit.

The nitrate–nitrite–NO conversion pathway has been extensively studied to show that nitrite can serve as a pool for NO.6,7 Although it would be valuable to investigate the role of H2S donors in the treatment for ASLD, we believe that in patients with ASLD who may have congenital deficiency of NO, treatment with NO supplementation would be more efficacious. We agree that systematic long-term clinical studies in randomized controlled settings would be necessary to assess the efficacy of NO supplementation in the prevention and treatment of ASLD complications such as hypertension.

Disclosure

The authors declare no conflict of interest.