Augmented adrenergic vasoconstriction in hypertensive diabetic obese Zucker rats

2002 ◽  
Vol 282 (3) ◽  
pp. H816-H820 ◽  
Author(s):  
David W. Stepp ◽  
Jefferson C. Frisbee
Keyword(s):  
Skeletal Muscle ◽  
Endothelial Nitric Oxide Synthase ◽  
Vessel Diameter ◽  
Zucker Rats ◽  
Obese Zucker Rats ◽  
Arterial Constriction ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

This study examined skeletal muscle microvessel reactivity to constrictor stimuli in obese (OZR) versus lean Zucker rats (LZR). Gracilis arteries from both rat groups were isolated, cannulated with glass micropipettes, and viewed via television microscopy. Changes in vessel diameter were measured with a video micrometer. Arterial constriction to norepinephrine was elevated in OZR versus LZR, although vasoconstrictor reactivity to endothelin and angiotensin II was unaltered. Differences in reactivity between vessels of LZR and OZR were not explained by the loss of either endothelial nitric oxide synthase or β-adrenergic receptor function. Reactivity of in situ cremasteric arterioles of OZR to norepinephrine was elevated versus LZR. Treatment with prazosin increased the diameter of in vivo gracilis arteries of OZR to levels determined in LZR and also normalized blood pressure in OZR. These results suggest that the constrictor reactivity of skeletal muscle microvessels in OZR is heightened in response to α-adrenergic stimuli and that development of diabetes in OZR may be associated with impaired skeletal muscle perfusion and hypertension due to microvessel hyperreactivity in response to sympathetic stimulation.

scholarly journals Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo

2010 ◽  
Vol 298 (5) ◽  
pp. R1399-R1408 ◽  
Author(s):  
Robert S. Lee-Young ◽  
Julio E. Ayala ◽  
Charles F. Hunley ◽  
Freyja D. James ◽  
Deanna P. Bracy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Metabolic Regulation ◽  
Acid Uptake ◽  
Enos Expression ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Endothelial nitric oxide synthase (eNOS) is associated with a number of physiological functions involved in the regulation of metabolism; however, the functional role of eNOS is poorly understood. We tested the hypothesis that eNOS is critical to muscle cell signaling and fuel usage during exercise in vivo, using 16-wk-old catheterized (carotid artery and jugular vein) C57BL/6J mice with wild-type (WT), partial (+/−), or no expression (−/−) of eNOS. Quantitative reductions in eNOS expression (∼40%) elicited many of the phenotypic effects observed in enos−/− mice under fasted, sedentary conditions, with expression of oxidative phosphorylation complexes I to V and ATP levels being decreased, and total NOS activity and Ca2+/CaM kinase II Thr286 phosphorylation being increased in skeletal muscle. Despite these alterations, exercise tolerance was markedly impaired in enos−/− mice during an acute 30-min bout of exercise. An eNOS-dependent effect was observed with regard to AMP-activated protein kinase signaling and muscle perfusion. Muscle glucose and long-chain fatty acid uptake, and hepatic and skeletal muscle glycogenolysis during the exercise bout was markedly accelerated in enos−/− mice compared with enos+/− and WT mice. Correspondingly, enos−/− mice exhibited hypoglycemia during exercise. Thus, the ablation of eNOS alters a number of physiological processes that result in impaired exercise capacity in vivo. The finding that a partial reduction in eNOS expression is sufficient to induce many of the changes associated with ablation of eNOS has implications for chronic metabolic diseases, such as obesity and insulin resistance, which are associated with reduced eNOS expression.

Increasing dihydrobiopterin causes dysfunction of endothelial nitric oxide synthase in rats in vivo

2011 ◽  
Vol 301 (3) ◽  
pp. H721-H729 ◽  
Author(s):  
Katsuhiko Noguchi ◽  
Naobumi Hamadate ◽  
Toshihiro Matsuzaki ◽  
Mayuko Sakanashi ◽  
Junko Nakasone ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Control Treatment ◽  
Enos Uncoupling ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
First Time

An elevation of oxidized forms of tetrahydrobiopterin (BH4), especially dihydrobiopterin (BH2), has been reported in the setting of oxidative stress, such as arteriosclerotic/atherosclerotic disorders, where endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH2 in the regulation of eNOS activity in vivo remains to be evaluated. This study was designed to clarify whether increasing BH2 concentration causes endothelial dysfunction in rats. To increase vascular BH2 levels, the BH2 precursor sepiapterin (SEP) was intravenously given after the administration of the specific dihydrofolate reductase inhibitor methotrexate (MTX) to block intracellular conversion of BH2 to BH4. MTX/SEP treatment did not significantly affect aortic BH4 levels compared with control treatment. However, MTX/SEP treatment markedly augmented aortic BH2 levels (291.1 ± 29.2 vs. 33.4 ± 6.4 pmol/g, P < 0.01) in association with moderate hypertension. Treatment with MTX alone did not significantly alter blood pressure or BH4 levels but decreased the BH4-to-BH2 ratio. Treatment with MTX/SEP, but not with MTX alone, impaired ACh-induced vasodilator and depressor responses compared with the control treatment (both P < 0.05) and also aggravated ACh-induced endothelium-dependent relaxations ( P < 0.05) of isolated aortas without affecting sodium nitroprusside-induced endothelium-independent relaxations. Importantly, MTX/SEP treatment significantly enhanced aortic superoxide production, which was diminished by NOS inhibitor treatment, and the impaired ACh-induced relaxations were reversed with SOD ( P < 0.05), suggesting the involvement of eNOS uncoupling. These results indicate, for the first time, that increasing BH2 causes eNOS dysfunction in vivo even in the absence of BH4 deficiency, demonstrating a novel insight into the regulation of endothelial function.

EDHF mediates flow-induced dilation in skeletal muscle arterioles of female eNOS-KO mice

2001 ◽  
Vol 280 (6) ◽  
pp. H2462-H2469 ◽  
Author(s):  
An Huang ◽  
Dong Sun ◽  
Mairead A. Carroll ◽  
Houli Jiang ◽  
Carolyn J. Smith ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Endothelial Nitric Oxide Synthase ◽  
Hexanoic Acid ◽  
Gracilis Muscle ◽  
Wild Type ◽  
Basal Release ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Cytochrome P 450

Vasodilation to increases in flow was studied in isolated gracilis muscle arterioles of female endothelial nitric oxide synthase (eNOS)-knockout (KO) and female wild-type (WT) mice. Dilation to flow (0–10 μl/min) was similar in the two groups, yet calculated wall shear stress was significantly greater in arterioles of eNOS-KO than in arterioles of WT mice. Indomethacin, which inhibited flow-induced dilation in vessels of WT mice by ∼40%, did not affect the responses of eNOS-KO mice, whereas miconazole and 6-(2-proparglyoxyphenyl)hexanoic acid (PPOH) abolished the responses. Basal release of epoxyeicosatrienonic acids from arterioles was inhibited by PPOH. Iberiotoxin eliminated flow-induced dilation in arterioles of eNOS-KO mice but had no effect on arterioles of WT mice. In WT mice, neither N ω-nitro-l-arginine methyl ester nor miconazole alone affected flow-induced dilation. Combination of both inhibitors inhibited the responses by ∼50%. 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ) alone inhibited flow-induced dilation by ∼49%. ODQ + indomethacin eliminated the responses. Thus, in arterioles of female WT mice, nitric oxide and prostaglandins mediate flow-induced dilation. When eNOS is inhibited, endothelium-derived hyperpolarizing factor substitutes for nitric oxide. In female eNOS-KO mice, metabolites of cytochrome P-450, via activation of large-conductance Ca2+-activated K+ channels of smooth muscle, mediate entirely the arteriolar dilation to flow.

Chronic rosiglitazone treatment restores AMPKα2 activity in insulin-resistant rat skeletal muscle

2006 ◽  
Vol 290 (2) ◽  
pp. E251-E257 ◽  
Author(s):  
Sarah J. Lessard ◽  
Zhi-Ping Chen ◽  
Matthew J. Watt ◽  
Michael Hashem ◽  
Julianne J. Reid ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Zucker Rats ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ampk Signaling ◽  
Palmitate Oxidation ◽  
Insulin Resistant ◽  
Obese Zucker Rats

Rosiglitazone (RSG) is an insulin-sensitizing thiazolidinedione (TZD) that exerts peroxisome proliferator-activated receptor-γ (PPARγ)-dependent and -independent effects. We tested the hypothesis that part of the insulin-sensitizing effect of RSG is mediated through the action of AMP-activated protein kinase (AMPK). First, we determined the effect of acute (30–60 min) incubation of L6 myotubes with RSG on AMPK regulation and palmitate oxidation. Compared with control (DMSO), 200 μM RSG increased ( P < 0.05) AMPKα1 activity and phosphorylation of AMPK (Thr172). In addition, acetyl-CoA carboxylase (Ser218) phosphorylation and palmitate oxidation were increased ( P < 0.05) in these cells. To investigate the effects of chronic RSG treatment on AMPK regulation in skeletal muscle in vivo, obese Zucker rats were randomly allocated into two experimental groups: control and RSG. Lean Zucker rats were treated with vehicle and acted as a control group for obese Zucker rats. Rats were dosed daily for 6 wk with either vehicle (0.5% carboxymethylcellulose, 100 μl/100 g body mass), or 3 mg/kg RSG. AMPKα1 activity was similar in muscle from lean and obese animals and was unaffected by RSG treatment. AMPKα2 activity was ∼25% lower in obese vs. lean animals ( P < 0.05) but was normalized to control values after RSG treatment. ACC phosphorylation was decreased with obesity ( P < 0.05) but restored to the level of lean controls with RSG treatment. Our data demonstrate that RSG restores AMPK signaling in skeletal muscle of insulin-resistant obese Zucker rats.

scholarly journals The Key Role of Caveolin-1 in Estrogen-Mediated Regulation of Endothelial Nitric Oxide Synthase Function in Cerebral Arterioles In vivo

2001 ◽  
Vol 21 (8) ◽  
pp. 907-913 ◽  
Author(s):  
Hao-Liang Xu ◽  
Elena Galea ◽  
Roberto A. Santizo ◽  
Verna L. Baughman ◽  
Dale A. Pelligrino
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Functional Activity ◽  
Endothelial Nitric Oxide Synthase ◽  
Down Regulation ◽  
Caveolin 1 ◽  
Cerebral Arterioles ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The marked impairment in cerebrovascular endothelial nitric oxide synthase (eNOS) function that develops after ovariectomy may relate to the observation that the abundance of cerebral vascular eNOS and its endogenous inhibitor, caveolin-1, vary in opposite directions with chronic changes in estrogen status. The authors endeavored, therefore, to establish a link between these correlative findings by independently manipulating, in ovariectomized female rats, eNOS and caveolin-1 expression, while monitoring agonist (acetylcholine)-stimulated eNOS functional activity. In the current study, the authors showed that individually neither the up-regulation of eNOS (through simvastatin treatment), nor the down-regulation of caveolin-1 (through antisense oligonucleotide administration) is capable of restoring eNOS function in pial arterioles in vivo in these estrogen-depleted rats. Only when eNOS up-regulation and caveolin-1 down-regulation are combined is activity normalized. These results establish a mechanistic link between the estrogen-associated divergent changes in the abundance of caveolin-1 and eNOS protein and eNOS functional activity in cerebral arterioles.

Enhanced arteriolar α-adrenergic constriction impairs dilator responses and skeletal muscle perfusion in obese Zucker rats

2004 ◽  
Vol 97 (2) ◽  
pp. 764-772 ◽  
Author(s):  
Jefferson C. Frisbee
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Gastrocnemius Muscle ◽  
Muscle Blood Flow ◽  
Zucker Rats ◽  
Metabolic Demand ◽  
Obese Zucker Rats ◽  
Isometric Twitch ◽  
Gastrocnemius Muscles

The present study tested the hypothesis that enhanced vascular α-adrenergic constriction in obese Zucker rats (OZR) impairs arteriolar dilation and perfusion of skeletal muscle at rest and with increased metabolic demand. In lean Zucker rats (LZR) and OZR, isolated gracilis arterioles were viewed via television microscopy, and the contralateral cremaster muscle or gastrocnemius muscle was prepared for study in situ. Gracilis and cremasteric arterioles were challenged with dilator stimuli under control conditions and after blockade of α-adrenoreceptors with prazosin, phentolamine, or yohimbine. Gastrocnemius muscles performed isometric twitch contractions of increasing frequency, and perfusion was continuously monitored. In OZR, dilator responses of arterioles to hypoxia (gracilis), wall shear rate (cremaster), acetylcholine, and iloprost (both) were impaired vs. LZR. Treatment with prazosin and phentolamine (and in cremasteric arterioles only, yohimbine) improved arteriolar reactivity to these stimuli in OZR, although responses remained impaired vs. LZR. Gastrocnemius muscle blood flow was reduced at rest in OZR; this was corrected with intravenous infusion of phentolamine or prazosin. At all contraction frequencies, blood flow was reduced in OZR vs. LZR; this was improved by infusion of phentolamine or prazosin at low-moderate metabolic demand only (1 and 3 Hz). At 5 Hz, adrenoreceptor blockade did not alter blood flow in OZR from levels in untreated rats. These results suggest that enhanced α-adrenergic constriction of arterioles of OZR contributes to impaired dilator responses and reduced muscle blood flow at rest and with mild-moderate (although not with large) elevations in metabolic demand.

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