scholarly journals Distinct temporal phases of microvascular rarefaction in skeletal muscle of obese Zucker rats

2014 ◽  
Vol 307 (12) ◽  
pp. H1714-H1728 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
Adam G. Goodwill ◽  
Stephanie J. Frisbee ◽  
Joshua T. Butcher ◽  
Robert W. Brock ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Leukocyte Adhesion ◽  
Oxidant Stress ◽  
Therapeutic Interventions ◽  
Zucker Rats ◽  
Tnf Α ◽  
Obese Zucker Rats ◽  
No Bioavailability ◽  
Microvascular Rarefaction

Evolution of metabolic syndrome is associated with a progressive reduction in skeletal muscle microvessel density, known as rarefaction. Although contributing to impairments to mass transport and exchange, the temporal development of rarefaction and the contributing mechanisms that lead to microvessel loss are both unclear and critical areas for investigation. Although previous work suggests that rarefaction severity in obese Zucker rats (OZR) is predicted by the chronic loss of vascular nitric oxide (NO) bioavailability, we have determined that this hides a biphasic development of rarefaction, with both early and late components. Although the total extent of rarefaction was well predicted by the loss in NO bioavailability, the early pulse of rarefaction developed before a loss of NO bioavailability and was associated with altered venular function (increased leukocyte adhesion/rolling), and early elevation in oxidant stress, TNF-α levels, and the vascular production of thromboxane A2 (TxA2). Chronic inhibition of TNF-α blunted the severity of rarefaction and also reduced vascular oxidant stress and TxA2 production. Chronic blockade of the actions of TxA2 also blunted rarefaction, but did not impact oxidant stress or inflammation, suggesting that TxA2 is a downstream outcome of elevated reactive oxygen species and inflammation. If chronic blockade of TxA2 is terminated, microvascular rarefaction in OZR skeletal muscle resumes, but at a reduced rate despite low NO bioavailability. These results suggest that therapeutic interventions against inflammation and TxA2 under conditions where metabolic syndrome severity is moderate or mild may prevent the development of a condition of accelerated microvessel loss with metabolic syndrome.

scholarly journals Integration of skeletal muscle resistance arteriolar reactivity for perfusion responses in the metabolic syndrome

2009 ◽  
Vol 296 (6) ◽  
pp. R1771-R1782 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
John M. Hollander ◽  
Robert W. Brock ◽  
Han-Gang Yu ◽  
Matthew A. Boegehold
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Vascular Reactivity ◽  
Oxidant Stress ◽  
Zucker Rats ◽  
Minimal Effect ◽  
Metabolic Demand ◽  
The Metabolic Syndrome ◽  
The Impact

Previous study suggests that with evolution of the metabolic syndrome, patterns of arteriolar reactivity are profoundly altered and may constrain functional hyperemia. This study investigated interactions between parameters of vascular reactivity at two levels of resistance arterioles in obese Zucker rats (OZR), translating these observations into perfusion regulation for in situ skeletal muscle. Dilation of isolated and in situ resistance arterioles from OZR to acetylcholine, arachidonic acid (AA), and hypoxia (isolated arterioles only) were blunted vs. lean Zucker rats (LZR), although dilation to adenosine was intact. Increased adrenergic tone (phenylephrine) or intralumenal pressure (ILP) impaired dilation in both strains (OZR>LZR). Treatment of OZR arterioles with Tempol (superoxide dismutase mimetic) or SQ-29548 (prostaglandin H2/thromboxane A2 receptor antagonist) improved dilator reactivity under control conditions and with increased ILP, but had minimal effect with increased adrenergic tone. Arteriolar dilation to adenosine was well maintained in both strains under all conditions. For in situ cremasteric arterioles, muscle contraction-induced elevations in metabolic demand elicited arteriolar dilations and hyperemic responses that were blunted in OZR vs. LZR, although distal parallel arterioles were characterized by heterogeneous dilator and perfusion responses. α-Adrenoreceptor blockade improved outcomes at rest but had minimal effect with elevated metabolic demand. Treatment with Tempol or SQ-29548 had minimal impact at rest, but lessened distal arteriolar perfusion heterogeneity with increased metabolic demand. In blood-perfused gastrocnemius of OZR, perfusion was constrained primarily by adrenergic tone, while myogenic activation and endothelium-dependent dilation did not appear to contribute significantly to ischemia. These results of this novel, integrated approach suggest that adrenergic tone and metabolic dilation are robust determinants of bulk perfusion to skeletal muscle of OZR, while endothelial dysfunction may more strongly regulate perfusion distribution homogeneity via the impact of oxidant stress and AA metabolism.

scholarly journals Increased vascular thromboxane generation impairs dilation of skeletal muscle arterioles of obese Zucker rats with reduced oxygen tension

2008 ◽  
Vol 295 (4) ◽  
pp. H1522-H1528 ◽  
Author(s):  
Adam G. Goodwill ◽  
Milinda E. James ◽  
Jefferson C. Frisbee
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Arachidonic Acid ◽  
Polyethylene Glycol ◽  
Nitric Oxide Synthase ◽  
Oxidant Stress ◽  
Zucker Rats ◽  
Obese Zucker Rats ◽  
Oxide Synthase

This study determined if altered vascular prostacyclin (PGI2) and/or thromboxane A2 (TxA2) production with reduced Po2 contributes to impaired hypoxic dilation of skeletal muscle resistance arterioles of obese Zucker rats (OZRs) versus lean Zucker rats (LZRs). Mechanical responses were assessed in isolated gracilis muscle arterioles following reductions in Po2 under control conditions and following pharmacological interventions inhibiting arachidonic acid metabolism and nitric oxide synthase and alleviating elevated vascular oxidant stress. The production of arachidonic acid metabolites was assessed using pooled arteries from OZRs and LZRs in response to reduced Po2. Hypoxic dilation, endothelium-dependent in both strains, was attenuated in OZRs versus LZRs. Nitric oxide synthase inhibition had no significant impact on hypoxic dilation in either strain. Cyclooxygenase inhibition dramatically reduced hypoxic dilation in LZRs and abolished responses in OZRs. Treatment of arterioles from OZRs with polyethylene glycol-superoxide dismutase improved hypoxic dilation, and this improvement was entirely cyclooxygenase dependent. Vascular PGI2 production with reduced Po2 was similar between strains, although TxA2 production was increased in OZRs, a difference that was attenuated by treatment of vessels from OZRs with polyethylene glycol-superoxide dismutase. Both blockade of PGH2/TxA2 receptors and inhibition of thromboxane synthase increased hypoxic dilation in OZR arterioles. These results suggest that a contributing mechanism underlying impaired hypoxic dilation of skeletal muscle arterioles of OZRs may be an increased vascular production of TxA2, which competes against the vasodilator influences of PGI2. These results also suggest that the elevated vascular oxidant stress inherent in metabolic syndrome may contribute to the increased vascular TxA2 production and may blunt vascular sensitivity to PGI2.

Oxidant stress-induced increase in myogenic activation of skeletal muscle resistance arteries in obese Zucker rats

2002 ◽  
Vol 283 (6) ◽  
pp. H2160-H2168 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
Kristopher G. Maier ◽  
David W. Stepp
Keyword(s):  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Oxidant Stress ◽  
Intraluminal Pressure ◽  
Zucker Rats ◽  
Radical Scavengers ◽  
Resistance Arteries ◽  
Obese Zucker Rats ◽  
Cytochrome P 450

This study characterized myogenic activation of skeletal muscle (gracilis) resistance arteries from lean (LZR) and obese Zucker rats (OZR). Arteries from OZR exhibited increased myogenic activation versus LZR; this increase was impaired by endothelium denudation or nitric oxde synthase inhibition. Treatment of vessels with 17-octadecynoic acid impaired responses in both strains by comparable amounts. Dihydroethidine microfluorography indicated elevated vascular superoxide levels in OZR versus LZR; immunohistochemistry demonstrated elevated vascular nitrotyrosine levels in OZR, indicating increased peroxynitrite presence. Vessel treatment with oxidative radical scavengers (polythylene glycol-superoxide dismutase/catalase) or inhibition of Ca2+-activated K+(KCa) channels (iberiotoxin) did not alter myogenic activation in LZR but normalized activation in OZR. Application of peroxynitrite to vessels of OZR caused a greater vasoconstriction versus LZR; the response was impaired in OZR by elevated intraluminal pressure and was abolished in both strains by iberiotoxin. These results suggest that enhanced myogenic activation of gracilis arteries of OZR versus LZR 1) is not due to alterations in cytochrome P-450 contribution, and 2) may be due to elevated peroxynitrite levels inhibiting KCa channels following increased intraluminal pressure.

scholarly journals Impaired NO-dependent dilation of skeletal muscle arterioles in hypertensive diabetic obese Zucker rats

2001 ◽  
Vol 281 (3) ◽  
pp. H1304-H1311 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
David W. Stepp
Keyword(s):  
Skeletal Muscle ◽  
Shear Rate ◽  
Sodium Nitroprusside ◽  
Oxidant Stress ◽  
Wall Shear Rate ◽  
Zucker Rats ◽  
Obese Zucker Rats ◽  
Wall Shear ◽  
Dependent Flow

This study determined alterations to nitric oxide (NO)-dependent dilation of skeletal muscle arterioles from obese (OZR) versus lean Zucker rats (LZR). In situ cremaster muscle arterioles from both groups were viewed via television microscopy, and vessel dilation was measured with a video micrometer. Arteriolar dilation to acetylcholine and sodium nitroprusside was reduced in OZR versus LZR, although dilation to aprikalim was unaltered. NO-dependent flow-induced arteriolar dilation (via parallel microvessel occlusion) was attenuated in OZR, impairing arteriolar ability to regulate wall shear rate. Vascular superoxide levels, as assessed by dihydroethidine fluorescence, were elevated in OZR versus LZR. Treatment of cremaster muscles of OZR with the superoxide scavengers polyethylene glycol-superoxide dismutase and catalase improved arteriolar dilation to acetylcholine and sodium nitroprusside and restored flow-induced dilation and microvascular ability to regulate wall shear rate. These results suggest that NO-dependent dilation of skeletal muscle microvessels in OZR is impaired due to increased levels of superoxide. Taken together, these data suggest that the development of diabetes and hypertension in OZR may be associated with an impaired skeletal muscle perfusion via an elevated vascular oxidant stress.

Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome

2005 ◽  
Vol 289 (2) ◽  
pp. R307-R316 ◽  
Author(s):  
Jefferson C. Frisbee
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Microvessel Density ◽  
Gastrocnemius Muscle ◽  
Oxidant Stress ◽  
Zucker Rats ◽  
Metabolic Demand ◽  
The Metabolic Syndrome ◽  
Nitric Oxide Bioavailability

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 ∼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 Nω-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.

scholarly journals Exercise training blunts microvascular rarefaction in the metabolic syndrome

2006 ◽  
Vol 291 (5) ◽  
pp. H2483-H2492 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
Julie Balch Samora ◽  
Jonathan Peterson ◽  
Randall Bryner
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Gastrocnemius Muscle ◽  
Gelatin Zymography ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reduced Body ◽  
Markers Of Inflammation ◽  
The Metabolic Syndrome ◽  
No Bioavailability ◽  
Microvascular Rarefaction

Reduced skeletal muscle microvessel density (MVD) in the obese Zucker rat (OZR) model of the metabolic syndrome is a function of a chronic reduction in vascular nitric oxide (NO) bioavailability. Previous studies suggest that exercise can improve NO bioavailability and reduce chronic inflammation and that low vascular NO bioavailability may be associated with impaired angiogenic responses via increased matrix metalloproteinase (MMP)-2 and MMP-9 activity. As such, we hypothesized that chronic exercise (EX) would increase NO bioavailability in OZR and blunt microvascular rarefaction through reduced MMP activity, and potentially via altered plasma cytokine levels. Ten weeks of treadmill exercise (1 h/day, 5 days/wk, 22 m/min) reduced body mass and fasting insulin and triglyceride levels in EX-OZR vs. sedentary (SED) OZR. In EX-OZR, gastrocnemius muscle MVD was improved by 19 ± 4%, whereas skeletal muscle arteriolar dilation and conduit arterial methacholine-induced NO release were increased. In EX-OZR, functional hyperemia was improved vs. SED-OZR, and minimum vascular resistance within perfused gastrocnemius muscle was reduced, although no change in arteriolar stiffness was identified. Western blotting and gelatin zymography demonstrated that neither expression nor activity of MMP-2 or MMP-9 was altered in skeletal muscle of EX vs. SED animals. Plasma markers of inflammation associated with angiogenesis, monocyte chemoattractant protein-1 and IL-1β, were increased in SED-OZR and were reduced with training, whereas IL-13 was reduced in SED-OZR and increased with exercise. These data suggest that exercise-induced improvements in skeletal muscle MVD in OZR are associated with increased NO bioavailability and may stem from altered inflammatory profiles rather than MMP function.

Impaired skeletal muscle perfusion in obese Zucker rats

2003 ◽  
Vol 285 (5) ◽  
pp. R1124-R1134 ◽  
Author(s):  
Jefferson C. Frisbee
Keyword(s):  
Skeletal Muscle ◽  
Microvessel Density ◽  
Gastrocnemius Muscle ◽  
Oxidant Stress ◽  
Gracilis Muscle ◽  
Muscle Performance ◽  
Zucker Rats ◽  
Obese Zucker Rats ◽  
The Impact

Skeletal muscle arterioles from obese Zucker rats (OZR) exhibit oxidant stress-based alterations in reactivity, enhanced α-adrenergic constriction, and reduced distensibility vs. microvessels of lean Zucker rats (LZR). The present study determined the impact of these alterations for perfusion and performance of in situ skeletal muscle during periods of elevated metabolic demand. During bouts of isometric tetanic contractions, fatigue of in situ gastrocnemius muscle of OZR was increased vs. LZR; this was associated with impaired active hyperemia. In OZR, vasoactive responses of skeletal muscle arterioles from the contralateral gracilis muscle were impaired, due in part to elevated oxidant tone; reactivity was improved after treatment with polyethylene glycol-superoxide dismutase (PEGSOD). Arterioles of OZR also exhibited increased α-adrenergic sensitivity, which was abolished by treatment with phentolamine (10-5 M). Intravenous infusion of phentolamine (10 mg/kg) or PEG-SOD (2,000 U/kg) in OZR altered neither fatigue rates nor active hyperemia from untreated levels; however, combined infusion improved performance and hyperemia, although not to levels in LZR. Microvessel density in the contralateral gastrocnemius muscle, determined via histological analyses, was reduced by ∼25% in OZR vs. LZR, while individual arterioles from the contralateral gracilis muscle demonstrated reduced distensibility. These data suggest that altered arteriolar reactivity contributes to reduced muscle performance and active hyperemia in OZR. Further, despite pharmacological improvements in arteriolar reactivity, reduced skeletal muscle microvessel density and arteriolar distensibility also contribute substantially to reduced active hyperemia and potentially to impaired muscle performance.

scholarly journals Temporally distributed mechanisms for skeletal muscle microvascular rarefaction in metabolic syndrome (674.9)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Evan DeVallance ◽  
Paul Chantler ◽  
Adam Goodwill ◽  
Joshua Butcher ◽  
I. Olfert ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Microvascular Rarefaction

scholarly journals Increased Vascular Generation of Thromboxane A 2 : an Initiating Condition for Microvascular Rarefaction in Obese Zucker Rats?

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Adam G. Goodwill ◽  
Phoebe A. Stapleton ◽  
Stephanie J. Frisbee ◽  
Milinda E. James ◽  
Jefferson C. Frisbee
Keyword(s):  
Zucker Rats ◽  
Obese Zucker Rats ◽  
Microvascular Rarefaction
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