Rat Model Of Metabolic Syndrome Research Articles

Molecular and functional characterization of Kv 7 channels in penile arteries and corpus cavernosum of healthy and metabolic syndrome rats.

KCNQ-encoded voltage-dependent potassium channels (Kv 7) are involved in the regulation of vascular tone. In this study we evaluated the influence of Kv 7 channel activation on smooth muscle relaxation in rat penile arteries and corpus cavernosum from normal and spontaneously hypertensive, heart failure-prone (SHHF) rats - a rat model of human metabolic syndrome. Quantitative PCR and immunohistochemistry were used to determine the expression of KCNQ isoforms in penile tissue. Isometric tension was measured in intracavernous arterial rings and corpus cavernosum strips isolated from normal and SHHF rats. Transcripts for KCNQ3, KCNQ4 and KCNQ5 were detected in penile arteries and corpus cavernosum. KCNQ1 was only found in corpus cavernosum. Immunofluorescence signals to Kv 7.4 and Kv 7.5 were found in penile arteries, penile veins and corpus cavernosum. The Kv 7.2-7.5 activators, ML213 and BMS204352, relaxed pre-contracted penile arteries and corpus cavernosum independently of nitric oxide synthase or endothelium-derived hyperpolarization. Relaxations to sildenafil, a PDE5 inhibitor, and sodium nitroprusside (SNP), an nitric oxide donor, were reduced by blocking Kv 7 channels with linopirdine in penile arteries and corpus cavernosum. In SHHF rat penile arteries and corpus cavernosum, relaxations to ML213 and BMS204352 were attenuated, and the blocking effect of linopirdine on sildenafil-induced and SNP-induced relaxations reduced. KCNQ3, KCNQ4 and KCNQ5 were down-regulated, and KCNQ1 was up-regulated in corpus cavernosum from SHHF rats. KCNQ1-5 transcripts remained unchanged in penile arteries from SHHF rats. These data suggest that Kv 7 channels play a role in erectile function and contribute to the pathophysiology of erectile dysfunction, an early indicator of cardiovascular disease.

MTOR Inhibition: Reduced Insulin Secretion and Sensitivity in a Rat Model of Metabolic Syndrome.

Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and β -cell toxicity. Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, β-cell proliferation, and apoptosis were analyzed at 12 days. Islets were isolated to analyze insulin content, insulin secretion, and gene expression. After 12 days, SRL treatment only impaired IPGTT in a dose-dependent manner in OZR. Treatment prolongation induced increase of area under the curve of IPGTT in LZR and OZR; however, in contrast to OZR, LZR normalized glucose levels after 2 hours. The SRL reduced pancreas weight and islet proliferation in LZR and OZR as well as insulin content. Insulin secretion was only affected in OZR. Islets from OZR + SRL rats presented a downregulation of Neurod1, Pax4, and Ins2 gene. Genes related with insulin secretion remained unchanged or upregulated. In conditions that require adaptive β -cell proliferation, SRL might reveal harmful effects by blocking β -cell proliferation, insulin production and secretion. These effects disappeared when removing the therapy.

Synergistic reduction by metformin and atorvastatin combination of hepato-metabolic changes in rat model of metabolic syndrome

Metabolic syndrome (MetS) with the commonly associated non-alcoholic fatty liver disease (NAFLD) is an increasing health concern and hot topic in medical research. Together with lifestyle modification, metformin (MET) and statins are among drugs with potential therapeutic benefit. The aim of this study is to investigate the potential of synergistic combination of MET and atorvastatin (ATR) in rat model of MetS. Rats were fed on high-carbohydrate, high-fat (HCHF) diet for 16 weeks and either of MET, ATR, or their combination were administered from the beginning of the 9th week to the end of the study. Body weight, insulin resistance, plasma lipids, serum transaminases, TNF-α, leptin and adiponectin as well as liver histopatholo-gy were assessed. Both MET and ATR worked synergistically to reverse the biochemical and histological abnormalities of MetS and ameliorated steatohepatitis more than their individual effects. The present study clearly demonstrates a synergistic effect of MET and ATR combination to reverse hepato-metabolic abnormalities of MetS/NAFLD in rat model and calls for pursuing subsequent clinical studies to consolidate data at hand.

Osteocalcin in a rat model of metabolic syndrome

Osteocalcin (OC) is an osteoblast-derived vitamin K dependent protein. Recent studies have demonstrated that in mice it acts as a multifunctional hormone, increasing insulin secretion and beta cell proliferation and improving insulin sensitivity. Osteocalcin has been postulated to be metabolically active in its undercarboxylated form. Whether OC plays a similar metabolic role in the rat is currently unknown. The aim of the present study was to compare the levels of OC in intact rats and in rats with a diet-induced metabolic syndrome. A secondary objective was to look for correlations of OC with metabolic parameters. Two groups of rats were used. The control group received regular rat chow and plain water and the experimental group was fed a diet high in saturated fat and fructose. The duration of the experiment was 10 weeks. At the end of this period insulin tolerance test was performed. Serum lipids, insulin, leptin and both forms of OC, carboxylated and undercarboxylated, were determined. Metabolic syndrome was verified by increased visceral adiposity, elevated serum triglycerides, cholesterol and fasting blood glucose, positive insulin tolerance test at the 90th minute, higher serum insulin. In rats with metabolic syndrome undercarboxylated OC serum level was significantly reduced, whereas carboxylated OC level was unchanged. The ratio undercarboxylated OC/ carboxylated OC was also lower in the experimental group. Undercarboxylated OC and undercarboxylated OC/ carboxylated OC were inversely associated with blood glucose but not with other biochemical parameters. Our results partly support the hypothesis that undercarboxylated OC is implicated in energy regulation and suggest that this might be true also for the rat. More evidence is needed to determine the hormonal role of osteocalcin in this animal species. Adipobiology 2015; 7: 31-36 Key words : osteocalcin, metabolic syndrome, rat model, fasting blood glucose, correlations

Blunted flow-mediated responses and diminished nitric oxide synthase expression in lymphatic thoracic ducts of a rat model of metabolic syndrome

Shear-dependent inhibition of lymphatic thoracic duct (TD) contractility is principally mediated by nitric oxide (NO). Endothelial dysfunction and poor NO bioavailability are hallmarks of vasculature dysfunction in states of insulin resistance and metabolic syndrome (MetSyn). We tested the hypothesis that flow-dependent regulation of lymphatic contractility is impaired under conditions of MetSyn. We utilized a 7-wk high-fructose-fed male Sprague-Dawley rat model of MetSyn and determined the stretch- and flow-dependent contractile responses in an isobaric ex vivo TD preparation. TD diameters were tracked and contractile parameters were determined in response to different transmural pressures, imposed flow, exogenous NO stimulation by S-nitro-N-acetylpenicillamine (SNAP), and inhibition of NO synthase (NOS) by l-nitro-arginine methyl ester (l-NAME) and the reactive oxygen species (ROS) scavenging molecule 4-hydroxy-tempo (tempol). Expression of endothelial NO synthase (eNOS) in TD was determined using Western blot. Approximately 25% of the normal flow-mediated inhibition of contraction frequency was lost in TDs isolated from MetSyn rats despite a comparable SNAP response. Inhibition of NOS with l-NAME abolished the differences in the shear-dependent contraction frequency regulation between control and MetSyn TDs, whereas tempol did not restore the flow responses in MetSyn TDs. We found a significant reduction in eNOS expression in MetSyn TDs suggesting that diminished NO production is partially responsible for impaired flow response. Thus our data provide the first evidence that MetSyn conditions diminish eNOS expression in TD endothelium, thereby affecting the flow-mediated changes in TD lymphatic function.

Hydrogen peroxide activates store-operated Ca(2+) entry in coronary arteries.

Abnormal Ca(2+) metabolism has been involved in the pathogenesis of vascular dysfunction associated with oxidative stress. Here, we have investigated the actions of H2 O2 on store-operated Ca(2+) (SOC) entry in coronary arteries and assessed whether it is impaired in arteries from a rat model of metabolic syndrome. Simultaneous measurements of intracellular Ca(2+) concentration and contractile responses were made in coronary arteries from Wistar and obese Zucker rats, mounted in microvascular myographs, and the effects of H2 O2 were assessed. H2 O2 raised intracellular Ca(2+) concentrations, accompanied by simultaneous vasoconstriction that was markedly reduced in a Ca(2+) -free medium. Upon Ca(2+) re-addition, a nifedipine-resistant sustained Ca(2+) entry, not coupled to contraction, was obtained in endothelium-denuded coronary arteries. The effect of H2 O2 on this voltage-independent Ca(2+) influx was concentration-dependent, and high micromolar H2 O2 concentrations were inhibitory and reduced SOC entry evoked by inhibition of the sarcoplasmic reticulum ATPase (SERCA). H2 O2 -induced increases in Fura signals were mimicked by Ba(2+) and reduced by heparin, Gd(3+) ions and by Pyr6, a selective inhibitor of the Orai1-mediated Ca(2+) entry,. In coronary arteries from obese Zucker rats, intracellular Ca(2+) mobilization and SOC entry activated by acute exposure to H2 O2 were augmented and associated with local oxidative stress. H2 O2 exerted dual concentration-dependent stimulatory/inhibitory effects on store-operated, IP3 receptor-mediated and Orai1-mediated Ca(2+) entry, not coupled to vasoconstriction in coronary vascular smooth muscle. SOC entry activated by H2 O2 was enhanced and associated with vascular oxidative stress in coronary arteries in metabolic syndrome.

Mitigation of Insulin Resistance by Mangiferin in a Rat Model of Fructose-Induced Metabolic Syndrome Is Associated with Modulation of CD36 Redistribution in the Skeletal Muscle.

Mangiferin is one of the prominent active components responsible for the antidiabetic property of many traditional herbs, but its underlying mechanisms of action remain unclear. CD36 in skeletal muscle is known to contribute to the etiology of insulin resistance by facilitating fatty acid uptake. This study investigated the effect of mangiferin on insulin resistance. The results showed that treatment of Wistar-Kyoto rats with mangiferin (15 mg/kg, once daily, by oral gavage) for 7 weeks inhibited chronic liquid fructose consumption-induced increases in plasma insulin concentrations at the baseline and during oral glucose tolerance test (OGTT), and the homeostasis model assessment of insulin resistance index. It also suppressed the increases in fasted plasma nonesterified fatty acid (NEFA) concentration and the adipose tissue insulin resistance index. Mechanistically, mangiferin neither affected intakes of fructose and chow, and the increase in epididymal and perirenal fat, nor attenuated fructose-induced hypertension. In contrast, mangiferin attenuated fructose-induced acceleration of plasma NEFA clearance during OGTT, and tended to decrease excessive triglyceride accumulation in gastrocnemius. Immunofluorescence staining and subsequent rating of CD36-expressing fibers in gastrocnemius revealed that mangiferin restored fructose-stimulated sarcolemmal CD36 overexpression and decreased intracellular CD36 distribution. In addition, the effects of mangiferin on the parameters associated with insulin resistance and abnormal fatty acid metabolism were absent in the spontaneously hypertensive rats carrying numerous nonfunctional mutations in the CD36 gene. Thus, these results suggest that mangiferin treatment mitigates insulin resistance in a rat model of fructose-induced metabolic syndrome by modulating sarcolemmal and intracellular CD36 redistribution in the skeletal muscle.

Selective Heart Rate Reduction Improves Metabolic Syndrome-related Left Ventricular Diastolic Dysfunction.

Enhanced heart rate observed in metabolic syndrome (MS) contributes to the deterioration of left ventricular (LV) function via impaired LV filling and relaxation, increased myocardial O2 consumption, and reduced coronary perfusion. However, whether heart rate reduction (HRR) opposes LV dysfunction observed in MS is unknown. We assessed in Zucker fa/fa rats, a rat model of MS, the cardiovascular effects of HRR induced by the If current inhibitor S38844 (3 mg · kg(-1) · d(-1)). Delayed short-term (4 days) and long-term (90 days) HRR induced by S38844 reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relation, increased myocardial tissue perfusion, decreased myocardial oxidized glutathione levels, and preserved cardiac output, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relation, although only long-term S38844 opposed LV collagen accumulation. Long-term S38844 improved flow-induced endothelium-dependent dilatation of mesenteric arteries, while metabolic parameters, such as plasma glucose levels, and Hb1c, were never modified. In rats with MS, HRR induced by the If inhibitor S38844 improved LV diastolic function and endothelium-dependent vascular dilatation, independent from modifications in metabolic status. Moreover, this improvement in cardiac function involves not only immediate effects such as improved myocardial perfusion and reduced oxidative stress but also long-term effects such as modifications in the myocardial structure.

Antioxidant and anti hyperglycemic role of wine grape powder in rats fed with a high fructose diet.

BackgroundMetabolic syndrome is a growing worldwide health problem. We evaluated the effects of wine grape powder (WGP), rich in antioxidants and fiber, in a rat model of metabolic syndrome induced by a high fructose diet. We tested whether WGP supplementation may prevent glucose intolerance and decrease oxidative stress in rats fed with a high fructose diet.MethodsMale Sprague–Dawley rats weighing 180 g were divided into four groups according to their feeding protocols. Rats were fed with control diet (C), control plus 20 % WGP (C + WGP), 50 % high fructose (HF) or 50 % fructose plus 20 % WGP (HF + WGP) for 16 weeks. Blood glucose, insulin and triglycerides, weight, and arterial blood pressure were measured. Homeostasis model assessment (HOMA) index was calculated using insulin and glucose values. A glucose tolerance test was performed 2 days before the end of the experiment. As an index of oxidative stress, thiobarbituric acid reactive substances (TBARS) level was measured in plasma and kidney, and superoxide dismutase was measured in the kidney.ResultsThiobarbituric acid reactive substances in plasma and renal tissue were significantly higher when compared to the control group. In addition, the area under the curve of the glucose tolerance test was higher in HF fed animals. Furthermore, fasting blood glucose, plasma insulin levels, and the HOMA index, were also increased. WGP supplementation prevented these alterations in rats fed with the HF diet. We did not find any significant difference in body weight or systolic blood pressure in any of the groups.ConclusionsOur results show that WGP supplementation prevented hyperglycemia, insulin resistance and reduced oxidative stress in rats fed with HF diet. We propose that WGP may be used as a supplement in human food as well.

Green and Black Cardamom in a Diet-Induced Rat Model of Metabolic Syndrome

Both black (B) and green (G) cardamom are used as flavours during food preparation. This study investigated the responses to B and G in a diet-induced rat model of human metabolic syndrome. Male Wistar rats were fed either a corn starch-rich diet (C) or a high-carbohydrate, high-fat diet with increased simple sugars along with saturated and trans fats (H) for 16 weeks. H rats showed signs of metabolic syndrome leading to visceral obesity with hypertension, glucose intolerance, cardiovascular remodelling and nonalcoholic fatty liver disease. Food was supplemented with 3% dried B or G for the final eight weeks only. The major volatile components were the closely related terpenes, 1,8-cineole in B and α-terpinyl acetate in G. HB (high-carbohydrate, high-fat + black cardamom) rats showed marked reversal of diet-induced changes, with decreased visceral adiposity, total body fat mass, systolic blood pressure and plasma triglycerides, and structure and function of the heart and liver. In contrast, HG (high-carbohydrate, high-fat + green cardamom) rats increased visceral adiposity and total body fat mass, and increased heart and liver damage, without consistent improvement in the signs of metabolic syndrome. These results suggest that black cardamom is more effective in reversing the signs of metabolic syndrome than green cardamom.

Abstract P129: 20-HETE Antagonist, 20-SOLA, Restores Coronary Collateral Growth in the Metabolic Syndrome

We have previously shown that transient and repetitive ischemia-induced (RI) coronary collateral growth (CCG) was severely impaired in a metabolic syndrome rat model (JCR rat). Levels of 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome (CYP)-derived arachidonic acid metabolite are greatly elevated in hypertensive animal models and loosely associated with obesity in humans, but its levels in metabolic syndrome, especially in cardiovascular tissues, as well as its possible involvement in the regulation of collateral growth are unknown. In rats, CYP4A1 is the major enzyme responsible for the production of 20-HETE. In this study, we demonstrated that cardiac CYP4A1 expression (RT-PCR, Western blot and immunohistochemistry) and 20-HETE levels were markedly (10-fold) elevated in JCR vs. Sprague-Dawly (SD) rats in response to RI. Importantly, administration of an antagonist of 20-HETE, 20-SOLA, completely restored CCG in JCR rats (collateral flow was 86±1% of that in the normal zone (JCR+SOLA) vs. 21±2% (JCR) vs. 84±5% (SD), p<0.05). We conclude that 20-HETE is an important modulator of CCG in the metabolic syndrome where its myocardial tissue levels are highly elevated.

Ferulic Acid Alleviates Changes in a Rat Model of Metabolic Syndrome Induced by High-Carbohydrate, High-Fat Diet.

Metabolic syndrome is a cluster of metabolic abnormalities characterized by obesity, insulin resistance, hypertension and dyslipidemia. Ferulic acid (FA) is the major phenolic compound found in rice oil and various fruits and vegetables. In this study, we examined the beneficial effects of FA in minimizing insulin resistance, vascular dysfunction and remodeling in a rat model of high-carbohydrate, high-fat diet-induced metabolic changes, which is regarded as an analogue of metabolic syndrome (MS) in man. Male Sprague-Dawley rats were fed a high carbohydrate, high fat (HCHF) diet and 15% fructose in drinking water for 16 weeks, where control rats were fed with standard chow diet and tap water. FA (30 or 60 mg/kg) was orally administered to the HCHF and control rats during the last six weeks of the study. We observed that FA significantly improved insulin sensitivity and lipid profiles, and reduced elevated blood pressure, compared to untreated controls (p < 0.05). Moreover, FA also improved vascular function and prevented vascular remodeling of mesenteric arteries. The effects of FA in HCHF-induced MS may be realized through suppression of oxidative stress by down-regulation of p47phox, increased nitric oxide (NO) bioavailability with up-regulation of endothelial nitric oxide synthase (eNOS) and suppression of tumor necrosis factor-α (TNF-α). Our results suggest that supplementation of FA may have health benefits by minimizing the cardiovascular complications of MS and alleviating its symptoms.

Blockade of glucocorticoid receptors with RU486 attenuates cardiac damage and adipose tissue inflammation in a rat model of metabolic syndrome.

Glucocorticoids are stress hormones that modulate metabolic, inflammatory and cardiovascular processes. We recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive (DS) and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated the effects of glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology and gene expression, as well as on glucose metabolism in this model. DS/obese rats were treated with the GR blocker RU486 (2 mg kg(-1) per day, subcutaneous) for 4 weeks beginning at 9 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+), or DS/lean) littermates of DS/obese rats served as controls. Treatment of DS/obese rats with RU486 attenuated left ventricular (LV) fibrosis and diastolic dysfunction, as well as cardiac oxidative stress and inflammation, without affecting hypertension or LV hypertrophy. Administration of RU486 to DS/obese rats also inhibited the upregulation of GR and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression at the mRNA and protein levels in the heart; it attenuated adiposity and adipose tissue inflammation, as well as the upregulation of GR and 11β-HSD1 mRNA and protein expression in adipose tissue; it ameliorated fasting hyperinsulinemia as well as insulin resistance and glucose intolerance. Our results thus implicate the glucocorticoid-GR axis in the pathophysiology of MetS, and they suggest that GR blockade has therapeutic potential for the treatment of this condition.

Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance.

Altered adiponectin signaling and chronic sympathetic hyperactivity have both been proposed as key factors in the pathogenesis of metabolic syndrome. We recently reported that activation of I1 imidazoline receptors (I1R) improves several symptoms of the metabolic syndrome through sympathoinhibition and increases adiponectin plasma levels in a rat model of metabolic syndrome (Fellmann L, Regnault V, Greney H, et al. J Pharmacol Exp Ther 346: 370-380, 2013). The present study was designed to explore the peripheral component of the beneficial actions of I1R ligands (i.e., sympathoinhibitory independent effects). Aged rats displaying insulin resistance and glucose intolerance were treated with LNP509, a peripherally acting I1R agonist. Glucose tolerance, insulin sensitivity, and adiponectin signaling were assessed at the end of the treatment. Direct actions of the ligand on hepatocyte and adipocyte signaling were also studied. LNP509 reduced the area under the curve of the intravenous glucose tolerance test and enhanced insulin hypoglycemic action and intracellular signaling (Akt phosphorylation), indicating improved glucose tolerance and insulin sensitivity. LNP509 stimulated adiponectin secretion acting at I1R on adipocytes, resulting in increased plasma levels of adiponectin; it also enhanced AMPK phosphorylation in hepatic tissues. Additionally, I1R activation on hepatocytes directly enhanced AMPK phosphorylation. To conclude, I1R ligands can improve insulin sensitivity acting peripherally, independently of sympathoinhibition; stimulation of adiponectin and AMPK pathways at insulin target tissues may account for this effect. This may open a promising new way for the treatment of the metabolic syndrome.

Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries. Defective autophagy of lipid droplets (LDs) in hepatocytes, also known as lipophagy, has recently been identified as a possible pathophysiological mechanism of NAFLD. Experimental and epidemiological evidence suggests that dietary polyphenols may prevent NAFLD. To address this hypothesis and analyze the underlying mechanisms, we supplemented bergamot polyphenol fraction (BPF) to cafeteria (CAF) diet-fed rats, a good model for pediatric metabolic syndrome and NAFLD. BPF treatment (50 mg/kg/day supplemented with drinking water, 3 months) potently counteracted the pathogenic increase of serum triglycerides and had moderate effects on blood glucose and obesity in this animal model. Importantly, BPF strongly reduced hepatic steatosis as documented by a significant decrease in total lipid content (−41.3%±12% S.E.M.), ultrasound examination and histological analysis of liver sections. The morphometric analysis of oil-red stained sections confirmed a dramatic reduction in LDs parameters such as total LD area (48.5%±15% S.E.M.) in hepatocytes from CAF+BPF rats. BPF-treated livers showed increased levels of LC3 and Beclin 1 and reduction of SQSTM1/p62, suggesting autophagy stimulation. Consistent with BPF stimulation of lipophagy, higher levels of LC3II were found in the LD subcellular fractions of BPF-expose livers. This study demonstrates that the liver and its lipid metabolism are the main targets of bergamot flavonoids, supporting the concept that supplementation of BPF is an effective strategy to prevent NAFLD.

Acute administration of single oral dose of grape seed polyphenols restores blood pressure in a rat model of metabolic syndrome: role of nitric oxide and prostacyclin

The aims of this study were to evaluate the antihypertensive effectiveness of different doses of grape seed polyphenols in cafeteria diet-fed hypertensive rats (CHRs) and to establish the mechanism involved in the blood pressure (BP) lowering effect of these compounds in this experimental model of metabolic syndrome (MS). Male 8-week-old Wistar rats were fed cafeteria or standard (ST) diet for 10 weeks. After this, the antihypertensive effect of a single oral administration of a polyphenol grape seed extract (GSPE) was tested at different doses (250, 375 and 500 mg/kg) in CHRs. BP was recorded before and 2, 4, 6, 8, 24 and 48 h post-administration. The hypotensive effect of GSPE was also proved in ST diet-fed rats. Additionally, in other experiment, CHRs were orally administered 375 mg/kg GSPE. Four hours post-administration, the rats were intraperitoneally administrated 30 mg/kg NG-nitro-L-arginine methyl ester (L-NAME) or 5 mg/kg indomethacin [inhibitors of nitric oxide (NO) and prostacyclin synthesis, respectively]. BP was recorded initially and 6 h post-administration. GSPE produced a decrease in SBP and DBP, the most effective dose (375 mg/kg) showing an antihypertensive effect in CHRs similar to the drug captopril, and did not affect BP of ST diet-fed rats. The antihypertensive effect was completely abolished by L-NAME and partially inhibited by indomethacin. GSPE acts as an antihypertensive agent in a rat model of hypertension associated with MS. The change in endothelium-derived NO availability is one of the mechanisms involved in the antihypertensive effect of GSPE in CHRs. Additionally, endothelial prostacyclin contributes to the effect of GSPE on arterial BP.

Depressed Sarcoplasmic Reticulum Activity Underlies Ca2+ Dyshomeostasis in A Rat Model of Metabolic Syndrome

High‐carbohydrate diet‐induced obesity and/or metabolic syndrom (MetS) is recognized as an independent risk factor for dysfunctioning of the heart. Although several mechanisms have been postulated for its identification, no precise mechanism is available yet for the cardiac remodeling and contractile dysfunction under MetS. Therefore, we aimed to investigate the role of sarcoplasmic reticulum (SR) on altered intracellular Ca2+ regulation in cardiomyocytes from MetS male rats, induced with high‐sucrose drinking water during 16‐week period. Basically, electrically‐stimulated Ca2+ transients and L‐type Ca2+‐currents (LTCC) were recorded in ventricular myocytes from MetS rats relative to myocytes from control rats. We also investigated SR‐Ca2+‐ATPase (SERCA) activity as well as phosphorylation levels of cardiac ryanodine receptor (RyR2) family proteins by Western blot analysis. The Ca2+ transients exhibited significantly reduced amplitude (~30%), and prolonged time courses (2‐fold) with no change in LTCC as well as depressed Ca2+ loading of SR (~55%) due to caffeine responses in cardiomyoctes from MetS rats with increased basal Ca2+ compared to aged‐matched control rats. Our data with caffeine responses under 0Na0Ca also demonstrated a depressed SERCA activity in MetS cardiomyocytes which supported further the data on a slowed cytosolic Ca2+ removal associated with a significant decrease in SERCA2‐mediated Ca2+ reuptake. Additionally, the data with tetracaine application assay was supporting a leaky‐RyR2 in cardiomyocytes from MetS group. Moreover, high phosphorylation levels of both RyR2 and phospholamban are supporting a depressed SR activity which underlies Ca2+ dyshomeostasis in MetS rat model.(Supported by TUBITAK‐SBAG‐111S042)

0205 : Exercise training prevents microvascular dysfunction in a rat model of diet-induced metabolic syndrome

Metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD). One important key feature underlying the pathophysiology of CVD is microvascular dysfunction. Although, exercise training is a well recognized strategy to reduce cardiovascular and metabolic disorders, the impact on MetS induced microvascular dysfunction is poorly described and the underlying mechanisms remain unknown. Thus, the aim of this work was to evaluate the effect of physical activity on microvascular reactivity in a rat model of MetS. Rats were fed with standard (Ctrl group) or high-fat and sucrose diet (HFS group) for 14 weeks. After 6 weeks, HFS rats were randomly assigned into 2 groups: sedentary (HFS) and trained group (HFS-Ex). In vivo endothelial function was evaluated by skin Laser Doppler technique associated to transcutaneous iontophoresis at 06 and 14 weeks. Body weight, metabolic parameters and blood pressure were also measured. High-fat and sucrose diet induced a significant body weight raise accompanied by the increase of serum level of glucose, triglycerides, HDL and LDL-cholesterol. All of these parameters were restored after 4 weeks of exercise training in HFS-Ex group. In addition, skin endothelium-dependent dilation, which was decreased in HFS compared to Ctrl, was prevented by exercise training. This result could be explained by increased level of eNOS expression and phosphorylation on its activation site (ser1177). These results mainly suggest that an exercise training strategy, which is able to partially correct metabolic disorders in a model of MetS in rats, also prevents in vivo microvascular dysfunction.

고과당식이 랫드모델에서 적하수오 투여에 의한 대사증후군 개선효과

Objectives : Polygoni Multiflori Radix (Jeokhasuo in Korean) is a Oriental traditional herbs widely used in East Asian countries. Overconsumption of fructose results in hypertension, dyslipidemia, obesity and impaired glucose tolerance which have documented as a risk of cardiovascular diseases. This experimental study was designed to investigate the beneficial effects of an ethanol extract from Polygoni Multiflori Radix (PMR) in high-fructose (HF) diet-induced metabolic syndrome rat model. Methods : Sprague-Dawley (SD) rats were divided into three groups; Control group, receiving regular diet and tap water, HF group, and HF + PMR group both receiving supplemented with 65% fructose (n=10), respectively. The HF + PMR group initially received HF diet with PMR (100 mg/kg/day) for 8 weeks. Results : PMR significantly prevented the metabolic disturbances such as hyperlipidemia, hypertension and impaired glucose tolerance. Chronic treatment with PMR significantly decreased body weight, fat weight and adipocyte size, suggesting a role of anti-obesity effect. PMR led to improve the hyperlipidemia through the increase in HDL cholesterol level as well as the decrease in triglyceride and LDL cholesterol level. In addition, PMR suppressed adhesion molecules and endothelin-1 (ET-1) expression in aorta resulting in the decrease of hypertension. In muscle tissue, PMR significantly recovered the HF-induced insulin resistance through increase of insulin receptor substrate-1 (IRS-1), p-<TEX>$AMPK{\alpha}1/2$</TEX>, and p-Akt expression. PMR improved HF-induced metabolic disorders and its action was caused by energy metabolism-mediated insulin signaling activation. Conclusions : These results demonstrate that PMR may be a beneficial therapeutic for metabolic syndrome through the improvement of hyperlipidemia, obesity, insulin resistance and hypertension.

Beneficial Effect of Rubus Coreanus Miq in a Rat Model of High Fructose Diet-induced Metabolic Syndrome

Overconsumption of fructose results in dyslipidemia, hypertension, which have documented as a risk of cardiovascular diseases. This experimental study was designed to investigate the beneficial effects of Rubus coreanus Miq .(RCM) in high-fructose diet-induced metabolic syndrome. Animals were divided into three groups; Control group fed regular diet and tap water, fructose groups were fed the 65% high-fructose (HF) diet with/without RCM 100 mg/kg/day for 8 weeks, respectively. Chronic treatment with RCM significantly decreased body weight, fat weight and adipocyte size. Moreover, RCM significantly prevented the development of the metabolic disturbances such as hyperlipidemia and hypertension. RCM also led to increase in high density lipoprotein level in the HF group. In addition, RCM suppressed vascular cell adhesion molecule-1 (VCAM-1) expression and significantly recovered the levels of endothelial nitric oxide synthase (eNOS) expression in aorta. These results demonstrates that RCM may be a beneficial therapeutic for metabolic syndrome through the improvement of hyperlipidemia, obesity, and hypertension.