Nitric oxide‐dependent attenuation of noradrenaline‐induced vasoconstriction is impaired in the canine model of Duchenne muscular dystrophy
| Autor: | Chady H. Hakim, Xiufang Pan, N. Nora Yang, Ronald L. Terjung, Dongsheng Duan, M. H. Laughlin, Kasun Kodippili, Hsiao T. Yang |
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| Rok vydání: | 2018 |
| Předmět: |
Male
musculoskeletal diseases 0301 basic medicine medicine.medical_specialty Contraction (grammar) Brachial Artery Physiology Duchenne muscular dystrophy Vasodilation Nitric Oxide Synthase Type I Nitric Oxide Nitric oxide Norepinephrine 03 medical and health sciences chemistry.chemical_compound Dogs 0302 clinical medicine Internal medicine medicine Animals Vasoconstrictor Agents Sarcolemma biology business.industry musculoskeletal system medicine.disease Muscular Dystrophy Duchenne body regions Nitric oxide synthase 030104 developmental biology Endocrinology nervous system chemistry Vasoconstriction cardiovascular system biology.protein Muscle Female medicine.symptom business Dystrophin 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Physiology. 596:5199-5216 |
| ISSN: | 1469-7793 0022-3751 |
| Popis: | 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. Abstract 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. |
| Databáze: | OpenAIRE |
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