Abstract 18830: Sodium Nitrate Recapitulates Sarcolemmal nNOS and Alleviates Functional Muscle Ischemia in Patients With Becker Muscular Dystrophy
Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is currently no treatment. Most BMD mutations disrupt sarcolemmal targeting of neuronal nitric oxide synthase (nNOS), causing functional muscle ischemia. In the mouse model of dystrophinopathy, chronic treatment with a nitric oxide (NO)-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischemia and improves many features of the dystrophic phenotype. As a first step toward clinical translation, we tested whether acute treatment with sodium nitrat--a simple inorganic NO donor without a NSIAD moiety-- will alleviate functional muscle ischemia in patients with BMD. In 11 men with BMD we first performed an open-label and then a placebo-controlled acute treatment trial. Reflex sympathetic vasoconstriction was measured as a decrease in muscle oxygenation by near infrared spectroscopy, evoked by lower-body negative pressure at rest and during rhythmic handgrip exercise. Without treatment, reflex vasoconstriction was not appropriately attenuated during exercise (ΔHbO2:-18.0±0.6 vs. -17.6±1.5 %; rest vs. exercise), producing functional muscle ischemia. With treatment, the ischemia was alleviated (ΔHbO2: -19.6±1.2 vs. -10.5±1.2; P <0.01, rest vs. exercise), and normal muscle blood flow regulation fully restored, by a single oral dose of sodium nitrate (8.4 mmol), which is converted by oral flora to nitrite (NO2-). These results were replicated in the placebo-controlled trial as well. Mechanistically, the data also show that circulating NO2- serves as an alternative NO donor when reduced by deoxyhemoglobin and deoxymyoglobin, whose intramuscular concentrations are low at rest and rise sharply when the muscle is exercised. Together, the data suggest that sodium nitrate recapitulates the normal vasomotor function of the missing sarcolemmal nNOS in patients with BMD, and constitutes a putative new therapy for patients with dystrophinopathy.
Author Disclosures: M.D. Nelson: None. F. Rader: None. X. Tang: None. T. Stabler: None. S. Shidban: None. R. Rosenberry: None. S. Hogan: None. R. Elashoff: None. J.D. Allen: None. R.G. Victor: None.
- © 2014 by American Heart Association, Inc.