Nitric oxide‐dependent attenuation of noradrenaline‐induced vasoconstriction is impaired in the canine model of Duchenne muscular dystrophy

• Published in: The Journal of physiology Vol. 596; no. 21; pp. 5199 - 5216
• Main Authors: Kodippili, Kasun, Hakim, Chady H., Yang, Hsiao T., Pan, Xiufang, Yang, N. Nora, Laughlin, Maurice H., Terjung, Ronald L., Duan, Dongsheng
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.11.2018; John Wiley and Sons Inc
• Subjects: Acetylcholine; Animal models; Blood flow; Canine model; Contraction; Dogs; Duchenne muscular dystrophy; Duchenne's muscular dystrophy; Dystrophin; Functional sympatholysis; Homeostasis; Ischemia; Isoforms; Muscle; Muscular dystrophy; Nitric oxide; Nitric oxide synthase; noradrenaline; Norepinephrine; Perfusion; Research Paper; Sarcolemma; Vasoconstriction; Vasodilatation; Functional sympatholysis; Canine model; Duchenne muscular dystrophy; Vasodilatation; Nitric oxide synthase; Acetylcholine; noradrenaline; vasoconstriction
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP275672

Key points We developed a novel method to study sympatholysis in dogs. We showed abolishment of sarcolemmal nNOS, and reduction of total nNOS and total eNOS in the canine Duchenne muscular dystrophy (DMD) model. We showed sympatholysis in dogs involving both nNOS‐derived NO‐dependent and NO‐independent mechanisms. We showed that the loss of sarcolemmal nNOS compromised sympatholysis in the canine DMD model. We showed that NO‐independent sympatholysis was not affected in the canine DMD model. The absence of dystrophin in Duchenne muscular dystrophy (DMD) leads to the delocalization of neuronal nitric oxide synthase (nNOS) from the sarcolemma. Sarcolemmal nNOS plays an important role in sympatholysis, a process of attenuating reflex sympathetic vasoconstriction during exercise to ensure blood perfusion in working muscle. Delocalization of nNOS compromises sympatholysis resulting in functional ischaemia and muscle damage in DMD patients and mouse models. Little is known about the contribution of membrane‐associated nNOS to blood flow regulation in dystrophin‐deficient DMD dogs. We tested the hypothesis that the loss of sarcolemmal nNOS abolishes protective sympatholysis in contracting muscle of affected dogs. Haemodynamic responses to noradrenaline in the brachial artery were evaluated at rest and during contraction in the absence and presence of NOS inhibitors. We found sympatholysis was significantly compromised in DMD dogs, as well as in normal dogs treated with a selective nNOS inhibitor, suggesting that the absence of sarcolemmal nNOS underlies defective sympatholysis in the canine DMD model. Surprisingly, inhibition of all NOS isoforms did not completely abolish sympatholysis in normal dogs, suggesting sympatholysis in canine muscle also involves NO‐independent mechanism(s). Our study established a foundation for using the dog model to test therapies aimed at restoring nNOS homeostasis in DMD. Key points We developed a novel method to study sympatholysis in dogs. We showed abolishment of sarcolemmal nNOS, and reduction of total nNOS and total eNOS in the canine Duchenne muscular dystrophy (DMD) model. We showed sympatholysis in dogs involving both nNOS‐derived NO‐dependent and NO‐independent mechanisms. We showed that the loss of sarcolemmal nNOS compromised sympatholysis in the canine DMD model. We showed that NO‐independent sympatholysis was not affected in the canine DMD model.