Résumé :
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Mutations in the gene encoding dystrophin cause X-linked Duchenne muscular dystrophy (DMD) characterized by progressive muscle weakness and respiratory or cardiac failure. In golden retriever dogs, a mutation in dystrophin gene leads to golden retriever muscular dystrophy (GRMD) presenting full spectrum of human pathology. Although some abnormalities in skeletal muscle and in heart are being recognized, little is known about vascular function in this model. To assess endothelial vascular function in this model and the effects of bradykinin (BK) that has been shown to exert a protective role in pacing-induced heart failure in dogs, 10 GRMD dogs with left ventricular dysfunction (indicated by a reduced fractional shortening: 28±2% vs 38±2% in GRMD and control dogs, respectively; p<0.001) and 8 control dogs were randomized to receive a perfusion of saline (vehicle) or BK (1?g/min) for 4 weeks. Before treatment in awake animals, acetylcholine (Ach, 3 ?g/kg) -induced reduction in mean arterial pressure was smaller in GRMD (-18±2 mmHg) than in control dogs (-29±2 mmHg, p<0.01). After 4 weeks of treatment, this response was still observed in vehicle-treated GRMD dogs while it was normalized in BK-treated GRMD, i.e., similar to control dogs. In isolated coronary artery rings, Ach (10-10-10-4 M)- induced relaxation was nearly abolished in vehicle-treated GRMD dogs while in BK-treated GRMD, relaxation to Ach was restored and similar to that obtained in control dogs. This response was not modified by indomethacin (indo, cyclooxygenase inhibitor) but was significantly blunted by N!-nitro-L-arginine [LNA, nitric oxide synthase (NOS) inhibitor] or LNA+indo. In addition, the endothelial NOS (eNOS) protein level and the cGMP content in the arterial tissue were significantly lower in vehicle-treated GRMD while, in BK-treated GRMD, they were similar to those observed in control dogs. These data indicate that the dystrophin deficiency-induced muscular dystrophy is associated with coronary and systemic endothelial dysfunction related to an impaired eNOS expression. Chronic BK perfusion restores vascular endothelial dysfunction through upregulation of eNOS, suggesting that BK-NO pathway is a potential target for treating vascular dysfunction in DMD patients.
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