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 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.

Impaired dilation of skeletal muscle microvessels to reduced oxygen tension in diabetic obese Zucker rats

2001 ◽  
Vol 281 (4) ◽  
pp. H1568-H1574 ◽  
Author(s):  
Jefferson C. Frisbee
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Superoxide Anion ◽  
Zucker Rats ◽  
Radical Scavengers ◽  
Resistance Arteries ◽  
Nitric Oxide Release ◽  
Obese Zucker Rats ◽  
Arterial Dilation ◽  
Oxide Synthase

This study determined alterations to hypoxic dilation of isolated skeletal muscle resistance arteries (gracilis arteries; viewed via television microscopy) from obese Zucker rats (OZR) compared with lean Zucker rats (LZR). Hypoxic dilation was reduced in OZR compared with LZR. Endothelium removal and cyclooxygenase inhibition (indomethacin) severely reduced this response in both groups, although nitric oxide synthase inhibition ( N ω-nitro-l-arginine methyl ester) reduced dilation in LZR only. Treatment of vessels with a PGH2-thromboxane A2 receptor antagonist had no effect on hypoxic dilation in either group. Arterial dilation to arachidonic acid, iloprost, acetylcholine, and sodium nitroprusside was reduced in OZR versus LZR, although dilation to forskolin and aprikalim was unaltered. Treatment of arteries from OZR with oxidative radical scavengers increased dilation to hypoxia and agonists, with no effect on responses in LZR. The restored hypoxic dilation in OZR was abolished by indomethacin. These results suggest that hypoxic dilation of skeletal muscle microvessels from LZR represents the summated effects of prostanoid and nitric oxide release, whereas the impaired response of vessels in OZR may reflect scavenging of PGI2 by superoxide anion.

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.

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.

Vascular adrenergic tone and structural narrowing constrain reactive hyperemia in skeletal muscle of obese Zucker rats

2006 ◽  
Vol 290 (5) ◽  
pp. H2066-H2074 ◽  
Author(s):  
Jefferson C. Frisbee
Keyword(s):  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Vascular Resistance ◽  
Perfusion Pressure ◽  
Reactive Hyperemia ◽  
Zucker Rats ◽  
Cremaster Muscle ◽  
Metabolic Demand ◽  
Obese Zucker Rats

Previous studies have demonstrated that skeletal muscle perfusion is impaired in obese Zucker rats (OZR) under control conditions and with elevated metabolic demand versus responses in lean Zucker rats (LZR). To further our understanding of processes contributing to impaired perfusion, we determined whether hyperemic responses following periods of occlusion were altered in skeletal muscle of OZR versus LZR. In isolated hindlimbs, basal blood flow in OZR was less than in LZR, and total perfusion responses after 30, 90, and 180 s of occlusion were reduced. Treatment of animals with an antioxidant (polythethylene glycol-superoxide dismutase) had no effect on reactive hyperemia, although blockade of α-adrenoreceptors (α1 > α2) improved responses to 30 and 90 s of occlusion; responses to 180 s of occlusion were unaltered. Pump perfusion of a dilated distal hindlimb demonstrated that increased volume flow elicited a greater increase in perfusion pressure in OZR versus LZR, suggesting structural contributions to an increased vascular resistance. Responses were comparable for in situ cremaster muscle because reactive hyperemia following serial arteriolar occlusion was attenuated in OZR versus LZR, treatment with polythethylene glycol-superoxide dismutase was ineffective, and hyperemic responses were improved following inhibition of α-adrenoreceptors (α1 > α2). Treatment of cremaster muscle with adenosine (10−3 M) caused flow to increase to a level comparable to that following 180 s of occlusion in both strains, although this level was reduced in OZR versus LZR. These results suggest that increased adrenergic tone may constrain reactive hyperemia in OZR with brief occlusion, although structural increases in vascular resistance can contribute to constrained perfusion after longer periods of occlusion.

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.

Targeting the Endothelial Ca2+ Toolkit to Rescue Endothelial Dysfunction in Obesity Associated-Hypertension

2020 ◽  
Vol 27 (2) ◽  
pp. 240-257 ◽  
Author(s):  
Francesco Moccia ◽  
Sharon Negri ◽  
Pawan Faris ◽  
Roberto Berra-Romani
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Endothelial Damage ◽  
Vascular Damage ◽  
Zucker Rats ◽  
Bibliographic Databases ◽  
Resistance Arteries ◽  
Small Resistance ◽  
Obese Zucker Rats ◽  
Transient Receptor

Background: Obesity is a major cardiovascular risk factor which dramatically impairs endothelium- dependent vasodilation and leads to hypertension and vascular damage. The impairment of the vasomotor response to extracellular autacoids, e.g., acetylcholine, mainly depends on the reduced Nitric Oxide (NO) bioavailability, which hampers vasorelaxation in large conduit arteries. In addition, obesity may affect Endothelium-Dependent Hyperpolarization (EDH), which drives vasorelaxation in small resistance arteries and arterioles. Of note, endothelial Ca2+ signals drive NO release and trigger EDH. Methods: A structured search of bibliographic databases was carried out to retrieve the most influential, recent articles on the impairment of vasorelaxation in animal models of obesity, including obese Zucker rats, and on the remodeling of the endothelial Ca2+ toolkit under conditions that mimic obesity. Furthermore, we searched for articles discussing how dietary manipulation could be exploited to rescue Ca2+-dependent vasodilation. Results: We found evidence that the endothelial Ca2+ could be severely affected by obese vessels. This rearrangement could contribute to endothelial damage and is likely to be involved in the disruption of vasorelaxant mechanisms. However, several Ca2+-permeable channels, including Vanilloid Transient Receptor Potential (TRPV) 1, 3 and 4 could be stimulated by several food components to stimulate vasorelaxation in obese individuals. Conclusion: The endothelial Ca2+ toolkit could be targeted to reduce vascular damage and rescue endothelium- dependent vasodilation in obese vessels. This hypothesis remains, however, to be probed on truly obese endothelial cells.

Impaired Ca 2+ handling in resistance arteries from genetically obese Zucker rats: Role of the PI3K, ERK1/2 and PKC signaling pathways

2018 ◽  
Vol 152 ◽  
pp. 114-128 ◽  
Author(s):  
Ana Sánchez ◽  
Cristina Contreras ◽  
Belén Climent ◽  
Alejandro Gutiérrez ◽  
Mercedes Muñoz ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Zucker Rats ◽  
Resistance Arteries ◽  
Pkc Signaling ◽  
Obese Zucker Rats

scholarly journals AVE0991, a Nonpeptide Angiotensin 1-7 Receptor Agonist, Improves Glucose Metabolism in the Skeletal Muscle of Obese Zucker Rats: Possible Involvement of Prooxidant/Antioxidant Mechanisms

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Viktoria Dobrocsyova ◽  
Miroslava Slamkova ◽  
Katarina Krskova ◽  
Lucia Balazova ◽  
Maciej Suski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Tolerance ◽  
Insulin Signaling ◽  
Receptor Agonist ◽  
Colorimetric Assay ◽  
Whole Body ◽  
Zucker Rats ◽  
Ros Generation ◽  
Morbidly Obese ◽  
Obese Zucker Rats

Angiotensin 1-7 (Ang 1-7) enhances insulin signaling and glucose transport activity in the skeletal muscle. The aim of our study was to evaluate the effect of AVE0991, a nonpeptide Mas receptor agonist, on the metabolic parameters, expression of RAS components and markers of oxidative stress, and insulin signaling in the skeletal morbidly obese rats. 33-week-old male obese Zucker rats were treated with vehicle and AVE0991 (0.5 mg/kg BW/day) via osmotic minipumps for two weeks. Gene expressions were determined by qPCR and/or Western blot analysis in musculus quadriceps. The enzymatic activities were detected flourometrically (aminopeptidase A) or by colorimetric assay kit (protein tyrosine phosphatase 1B). Administration of AVE0991 enhanced insulin signaling cascade in the skeletal muscle, reflected by improved whole-body glucose tolerance. It has been shown that reactive oxygen species (ROS) have insulin-mimetic action in muscle. The expression of renin receptor, transcription factor PLZF, and prooxidant genes was upregulated by AVE0991 accompanied by elevated expression of genes coding enzymes with antioxidant action. Our results show that AVE0991 administration activates genes involved in both ROS generation and clearance establishing a new prooxidant/antioxidant balance on a higher level, which might contribute to the improved insulin signaling pathway and glucose tolerance of obese Zucker rats.

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