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

Autor: Kodippili K; Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA., Hakim CH; Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA.; National Center for Advancing Translational Sciences (NCATS), Bethesda, MD, USA., Yang HT; Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA.; Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA., Pan X; Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA., Yang NN; National Center for Advancing Translational Sciences (NCATS), Bethesda, MD, USA., Laughlin MH; Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA., Terjung RL; Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA., Duan D; Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA.; Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA.; Department of Bioengineering, University of Missouri, Columbia, MO, USA.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2018 Nov; Vol. 596 (21), pp. 5199-5216. Date of Electronic Publication: 2018 Sep 20.
DOI: 10.1113/JP275672
Abstrakt: 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.
(© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)
Databáze: MEDLINE
Externí odkaz: