title: Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome.
abstract: This study tested the hypothesis that chronically elevated oxidant stress contributes to impaired active hyperemia in skeletal muscle of obese Zucker rats (OZR) vs. lean Zucker rats (LZR) through progressive deteriorations in microvascular structure. Twelve-week-old LZR and OZR were given 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol) in the drinking water for approximately 4 wk. Subsequently, perfusion of in situ gastrocnemius muscle was determined during incremental elevations in metabolic demand, while a contralateral skeletal muscle arteriole and the gastrocnemius muscle was removed to determine dilator reactivity, vessel wall mechanics, and microvessel density. Under control conditions, active hyperemia was impaired at all levels of metabolic demand in OZR, and this was correlated with a reduced microvessel density, increased arteriolar stiffness, and impaired dilator reactivity. Chronic tempol ingestion improved perfusion during moderate to high metabolic demand only and was associated with improved arteriolar reactivity and microvessel density; passive vessel mechanics were unaltered. Combined antioxidant therapy and nitric oxide synthase inhibition in OZR prevented much of the restored perfusion and microvessel density. In LZR, treatment with N(omega)-nitro-L-arginine methyl ester (L-NAME) hydrochloride and hydralazine (to prevent hypertension) impaired active hyperemia, dilator reactivity, and microvessel density, although arteriolar distensibility was not altered. These results suggest that with the development of the metabolic syndrome, chronic reductions in nitric oxide bioavailability, in part via the scavenging actions of oxidative free radicals, contribute to a loss of skeletal muscle microvessels, leading to impaired muscle perfusion with elevated metabolic demand.
authors.affiliation: Center for Interdisciplinary Research in Cardiovascular Science, Dept. of Physiology and Pharmacology, Robert C. Byrd Health Sciences Center, PO Box 9105, West Virginia University School of Medicine, Morgantown, WV 26505, USA. jfrisbee@hsc.wvu.edu
authors.forename: Jefferson C
authors.initials: JC
authors.lastname: Frisbee
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001682:Biological Availability; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006940:Hyperemia / Q000209:etiology / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008833:Microcirculation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood*; D009765:Obesity / Q000150:complications; D018384:Oxidative Stress; D051381:Rats; D011924:Rats, Zucker; D012039:Regional Blood Flow / Q000187:drug effects; D013113:Spin Labels; D014664:Vasodilation
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D013113:Spin Labels; D009569:Nitric Oxide; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester