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Am J Physiol Heart Circ Physiol 294: H1658-H1666, 2008. First published February 22, 2008; doi:10.1152/ajpheart.01206.2007
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Insulin resistance and impaired functional vasodilation in obese Zucker rats

Lusha Xiang, Jennifer Dearman, Sean R. Abram, Cory Carter, and Robert L. Hester

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi

Submitted 17 October 2007 ; accepted in final form 15 February 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Individuals with metabolic syndrome exhibit insulin resistance and an attenuated functional vasodilatory response to exercise. We have shown that impaired functional vasodilation in obese Zucker rats (OZRs) is associated with enhanced thromboxane receptor (TP)-mediated vasoconstriction. We hypothesized that insulin resistance, hyperglycemia/hyperlipidemia, and the resultant ROS are responsible for the increased TP-mediated vasoconstriction in OZRs, resulting in impaired functional vasodilation. Eleven-week-old male lean Zucker rats (LZRs) and OZRs were fed normal rat chow or chow containing rosiglitazone (5 mg·kg–1·day–1) for 2 wk. In another set of experiment, LZRs and OZRs were treated with 2 mM tempol (drinking water) for 7–10 days. After the treatments, spinotrapezius muscles were prepared, and arcade arteriolar diameters were measured following muscle stimulation and arachidonic acid (AA) application (10 µM) in the absence and presence of the TP antagonist SQ-29548 (1 µM). OZRs exhibited higher insulin, glucose, triglyceride, and superoxide levels and increased NADPH oxidase activity compared with LZRs. Functional and AA-induced vasodilations were impaired in OZRs. Rosiglitazone treatment improved insulin, glucose, triglyceride, and superoxide levels as well as NADHP oxidase activity in OZRs. Both rosiglitazone and tempol treatment improved vasodilatory responses in OZRs with no effect in LZRs. SQ-29548 treatment improved vasodilatory responses in nontreated OZRs with no effect in LZRs or treated OZRs. These results suggest that insulin resistance and the resultant increased ROS impair functional dilation in OZRs by increasing TP-mediated vasoconstriction.

arachidonic acid; prostacyclin; thromboxane; diabetes

OBESITY is related to a collection of risk factors for cardiovascular disease. Insulin resistance has been considered as a key factor that leads to a cascade of metabolic problems in obesity such as hyperglycemia, hyperlipidemia, and endothelial dysfunction, known collectively as metabolic syndrome. There is evidence that the increase in blood flow in response to muscle contraction, functional hyperemia, is attenuated in obese patients and animals (17, 20). A previous study (57) has shown impaired endothelium-dependent vasodilation and functional hyperemic responses in obese Zucker rats (OZRs). Several factors have been proposed to contribute to the impairment of endothelium-dependent vasodilation, such as increased inflammatory factors, ROS, and/or decreased nitric oxide (NO) function and bioavailability. However, the mechanism(s) responsible for the impairment of functional vasodilation still needs to be determined.

It is well established that arachidonic acid (AA) metabolites, vasodilators such as PGI2, and vasoconstrictors such as thromboxane A2 (TXA2) and its precursor PGH2 can affect vascular tone. Our previous studies (25, 38) demonstrated an important role of vasodilator prostaglandins in mediating functional vasodilation in normal animals. However, humans and animals with metabolic syndrome show altered AA metabolism, resulting in a "shift" from vasodilatory to vasoconstrictor metabolites of AA metabolism (13, 50). In a recent study (57), we have shown that functional and AA-mediated vasodilatory responses are impaired in OZRs, a model of metabolic syndrome, but these vasodilatory response are improved following thromboxane receptor (TP) inhibition with the TP antagonist SQ-29548. These results suggest that the attenuated functional hyperemic response is related to enhanced TP-mediated vasoconstriction (57). However, the physiological conditions responsible for the altered activation of TP during muscle contraction in OZRs are not clear. Previous studies (28, 60) have shown that insulin resistance and the resultant hyperglycemia and hyperlipidemia lead to enhanced ROS, resulting in altered AA metabolism and increased TP activation. Therefore, we hypothesized that insulin resistance, hyperglycemia/hyperlipidemia, and the resultant increased ROS in OZRs are responsible for the increased TP-mediated vasoconstriction, resulting in an impairment of functional vasodilation. We determined the effects of improving insulin resistance and ROS levels by rosiglitazone and tempol administration, respectively, on functional vasodilation in both lean Zucker rats (LZRs) and OZRs. We proposed that the improvement of hyperglycemia/hyperlipidemia and oxidant stress would normalize AA metabolism (10, 61) and lead to an increased functional vasodilatory response in OZRs.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals

Male LZRs and OZRs were acquired from Harlan Laboratories (44 LZRs and 44 OZRs). Experimental protocols for this study were approved by the Institutional Animal Care and Use Committee of the University of Mississippi Medical Center and were carried out according to both the National Institutes of Health Guide for the Care and Use of Laboratory Animals and guidelines of the Animal Welfare Act. All rats were housed two to three animals per cage at 22°C (12:12-h light-dark cycle) with free access to food and water.

Blood Plasma Glucose, Triglyceride, and Insulin Levels

LZRs (n = 14) and OZRs (n = 14) were treated with rosiglitazone for 2 wk, with six rats of each group used for vascular experiments, four rats of each group used for the oral glucose tolerance test (OGTT) and measurements of NADPH oxidase activity, and another four rats from each group for aortic superoxide fluorescence. Treated animals completely consumed the Teklab diet each day before being given regular chow to eat ad libitum. Each amount of food was calculated daily based on the weight of each animal such that LZRs consumed ~12 g/day of Teklab diet and OZRs consumed ~20 g/day of the Teklab diet, resulting in a treatment of 5 mg·kg–1·day–1. After 2 wk of rosiglitazone treatment, blood glucose levels were determined during an OGTT (50% dextrose solution, 3 ml/kg) in treated and nontreated rats that had been fasted for 8 h. Blood samples were withdrawn immediately before glucose application (by gavage) as well as after 15, 30, 60, 90, 120, and 240 min. In the other set of experiments, blood samples from the tail vein were collected from control LZRs and OZRs (12–13 wk, n = 6 rats/group) every 1 or 2 h from 1:00 PM until noon the next day, and glucose levels were measured. Animals had free access to regular or rosiglitazone-treated rat chow during the entire time. To determine the effect of rosiglitazone treatment on lipids, blood samples were collected from control and treated animals at 9:00–10:00 AM, and plasma triglyceride levels were averaged.

Blood samples were collected from the tail vein in conscious animals. Blood plasma glucose was analyzed using a Beckman Clinical Chemistry Analyzer (Beckman Instruments, Fullerton, CA). Plasma triglycerides were measured using a commercially available kit (L-type TG H, Wako Chemicals, Richmond, VA). After in vivo experiments had been completed, blood samples were collected via a cardiac injection from unconscious animals for insulin measurements. Plasma insulin levels were analyzed using radioimmunoassay kits (Linco Research, St. Louis, MO).

NADPH Oxidase Activity

Superoxide was measured in the renal cortex from control, rosiglitazone-treated, and tempol-treated LZRs and OZRs using lucigenin chemiluminescence. In brief, tissues were homogenized and centrifuged at 4°C at 12,000 g for 20 min. Homogenates were incubated with 5 µmol/l lucigenin (final concentration), and enzyme activity was measured with or without NADPH (100 µmol/l final concentration) in the reaction mixture through chemiluminescent detection using a Berthold luminometer, as previously described (16). A luminescence reading was obtained for an overall measuring time of 5 min for each sample. Enzyme activity is expressed in relative light units per minute and milligrams of wet tissue weight.

Oxidative Fluorescence

Following treatment, aortic segments were removed from all animals and place in cold physiological salt solution [PSS; containing (in mM) 119.0 NaCl, 4.7 KCl, 1.6 CaCl2, 1.18 NaH2PO4, 1.17 MgSO4, and 24.0 NaHCO3] to clear the surrounding connective tissue. Aortic segments were incubated in light-protected PSS (37°C) containing 5 µM dihydroethidium for 30 min. After a wash in dihydroethidium-free PSS, segments were split longitudinally and placed endothelium side down on a PSS-moistened coverslip (23). The medial smooth muscle layer was visualized, and images were obtained using a laser scanning confocal microscopy (Leica Microsystems) (59).

Microcirculatory Surgical Preparation

The right spinotrapezius muscle was prepared for experimental observation as previously described (31, 33, 58). In brief, rats were anesthetized with pentobarbital sodium (65 mg/kg ip), and the trachea was intubated. Animals spontaneously breathed a gas mixture containing 30% oxygen and 70% nitrogen. The left jugular vein was cannulated for the supplemental addition of anesthetic. At all times during the surgery and subsequent experiments, the spinotrapezius muscle was kept at in situ dimensions and continuously superfused with PSS of the following composition (in mM): 118.07 NaCl, 6.17 KCl, 2.55 CaCl2, and 25 NaHCO3 aerated with a 5% CO2-95% N2 gas mixture (pH 7.4, 35°C). At the completion of the experiments, animals were euthanized by a cardiac injection of pentobarbital sodium. Death was confirmed by a lack of a heartbeat and spontaneous breathing.

Experimental Measurements

Animals were allowed to stabilize for 15–30 min after the completion of the surgical procedures. Segments of arteriolar arcades with similar diameters were selected for analysis. The microcirculation of the spinotrapezius muscle was transilluminated and observed with a Nikon microscope fitted with a x10 water-immersion objective (numerical aperture = 0.30). The microscopic image was televised with a Dage closed-circuit television camera and displayed on a Sony monitor. The magnification of the image was x660 from the tissue to the monitor screen. Vessel diameter was measured using a Texas A&M video analyzer modified to function as a video micrometer. The resolution of this system was ±1 µm.

Muscle Stimulation

Two hooked silver-silver chloride electrodes (Grass Instruments) were placed at each end of the spinotrapezius and connected to a Grass S44 stimulator. Diameters of the vessels were obtained in the resting muscle and immediately after 2 min of electrical stimulation (4–5 V, 1 Hz).

Drugs and Vasoactive Agents

Rosiglitazone (Avandia), mixed with normal rat chow to yield a final concentration of 120 mg/kg food, was formulated by Harlan TekLab. 4-Hydroxy-2,2,6,6-tetramethylpiperidinyloxy (tempol; Sigma) was diluted in drinking water to yield a concentration of 2 mmol/l. AA, 1-benzylimidazole (thromboxane synthase inhibitor), U-46619 (TXA2 analog), and SQ-29548 (TP antagonist) were purchased form Cayman Chemical and stored in ethanol as stock solutions. During the experiments, the final concentration of ethanol in the superfusion solution was <0.1%.

Experiment Protocols

Role of thromboxane synthase and TP activity. To test the mechanism(s) for the enhanced TP activation in OZRs, 12- to 13-wk-old male LZRs and OZRs (n = 5 rats/group) were chosen for study. The right spinotrapezius muscle was prepared for the microcirculatory observations. Arteriolar diameter was obtained in the resting muscle and immediately after 2 min of electrical muscle stimulation. After a 15-min recovery period, AA (10 µM) was added to superfusion solution, and steady-state vasodilatory responses were measured. After the arteriole had returned to its resting diameter, the thromboxane synthase inhibitor 1-benzylimidazole (0.1 mM) was added to the superfusion solution (39). After a 30-min equilibration period, the muscle stimulation and AA protocols were repeated. After the arteriole had returned to its resting diameter, vasoconstrictor responses to increasing concentrations of thromboxane analog U-46619 (1, 10, and 100 nM) were determined. The superfusion solution was replaced with PSS containing 1-benzylimidazole (0.1 mM), and arterioles were allowed to return to baseline diameters between U-46619 concentrations. At the end of the experiment, adenosine (10 µM) was added to the superfusion solution to determine the maximal luminal diameter.

Effects of rosiglitazone and tempol treatment on vascular responses. After 2 wk of rosiglitazone treatment, the right spinotrapezius muscle was prepared for microcirculatory observations. Diameters of arterioles were obtained in the resting muscle and immediately after 2 min of electrical muscle stimulation. After a 15- to 30-min recovery period, AA (10 µM) was added to superfusion solution, and steady-state vasodilatory responses were measured. After the arteriole had returned to its resting diameter, the TP antagonist SQ-29548 (1 µM) was added to the superfusion solution. After a 30-min equilibration period, the muscle stimulation and AA protocols were repeated. At the end of the experiment, adenosine (10 µM) was added to the superfusion solution to determine the maximal luminal diameter. To determine the effects of tempol treatment on vasodilatory responses, five LZRs and five OZRs (11–12 wk old) were treated with tempol (2 mmol/l in drinking water) for 7–10 days (37 ± 3 mg·kg–1·day–1). After the treatment, the right spinotrapezius muscle was prepared for microcirculatory observations to test functional and AA-induced vasodilatory responses with or without the presence of SQ-29548. In the end of each experiment, blood samples were collected via a cardiac injection from unconscious animals for insulin measurements, and kidneys were taken for the measurement of NADPH oxidase activity.

Data Analysis and Statistical Methods

Arteriolar diameter data were collected at 1 Hz to a personal computer and stored to disk for later analysis. Basal and adenosine-induced diameters were compared using a t-test. The effects of 1-benzylimidazole and SQ-29548 on vasodilatory responses were analyzed using repeated-measures ANOVA. U-46619-induced vasoconstriction was compared between LZRs and OZRs using a t-test. All the other data were analyzed using two-way ANOVA. Where significant main effects occurred, individual groups were compared using the Holm-Sidak method. All data are means ± SD. Probability values of P < 0.05 were accepted as statistically significant for all comparisons.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Thromboxane Synthesis and TP Activity

In all cases, arteriolar diameter increased significantly following the muscle contraction or AA treatment (P < 0.05). Basal arteriolar diameters were not different between LZRs and OZRs (12 ± 1 µm for both groups, n = 5 LZRs and 5 OZRs). Functional (Fig. 1A) and AA-induced (Fig. 1B) dilations were significantly blunted in untreated OZRs compared with LZR controls. 1-Benzylimidazole treatment had no effect on basal diameters (12 ± 1 µm for both groups) or vasodilatory responses in either group (Fig. 1, A and B). U-46619 treatment induced similar vasoconstrictor responses in LZRs and OZRs at all concentrations (Fig. 1C).


Figure 1
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  		Fig. 1. A: functional vasodilation was significantly blunted in obese Zucker rats (OZRs) compared with lean Zucker rat (LZR) controls. 1-Benzylimidazole treatment did not alter vasodilatory responses in either group. *P < 0.05, LZRs vs. OZRs; n = 5 rats for both groups. B: arachidonic acid (AA)-induced dilation was significantly attenuated in OZRs compared with LZRs. 1-Benzylimidazole had no effect on vasodilation in either group. *P < 0.05, LZRs vs. OZRs; n = 5 rats for both groups. C: U46619 induced significant vasoconstriction in both LZRs and OZRs in a dose-dependent manner, whereas vasoconstrictor responses were not significantly different between LZRs and OZRs. P = 0.18 for 10 nM and P = 0.246 for 100 nM; n = 5 rats for both groups.

 
Effects of Rosiglitazone on Baseline Characteristics in LZRs and OZRs

The effects of rosiglitazone treatment on body weight and plasma insulin and triglyceride levels in LZRs and OZRs are shown in Table 1. Compared with LZR controls, OZRs exhibited significantly higher body weight and insulin and triglyceride levels. Rosiglitazone treatment normalized insulin and triglyceride levels in OZRs with no effect in LZRs. Body weights were not affected by rosiglitazone treatment in either LZRs or OZRs. There were no significant differences in basal or adenosine-induced diameters between control LZRs and OZRs. Neither rosiglitazone nor tempol treatment affected basal and maximal diameters in LZRs or OZRs. In all cases, SQ-29548 did not alter basal diameters, and vasodilatory responses to adenosine were not significantly different between groups (Table 2).


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  		Table 1. Baseline characteristics of control and rosiglitazone-treated rats

 

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  		Table 2. Arteriolar diameters of control, rosiglitazone-treated, and tempol-treated rats

 
Figure 2 shows glucose levels throughout the day in LZRs and OZRs. Blood glucose levels in OZRs were significantly higher than in LZRs. In the present study, the light-dark cycle was maintained at 12:12 h, respectively, beginning at 6:00 AM. Activity levels of rats were lower in the light period than in the dark period (15). The "hyperglycemic period," from ~5 PM to 10 PM in both control LZRs and OZRs implies an increased food intake.


Figure 2
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  		Fig. 2. Hourly blood glucose levels in control and treated animals. There was postprandial hyperglycemia from ~5 PM to 10 PM in control LZRs. Compared with LZRs, OZRs exhibited a higher and longer postprandial hyperglycemic period. *P < 0.05 vs. control LZRs; n = 6 rats/group.

 
Figure 3 shows the effects of rosiglitazone treatment on the glucose response during the OGTT in LZRs and OZRs. OZRs exhibited a higher and longer postprandial hyperglycemia period compared with LZR controls. Two weeks of rosiglitazone treatment normalized the glucose response in OZRs with no effects in LZRs. These results indicate that rosiglitazone had a specific effect to improve insulin resistance and reduce postprandial hyperglycemia.


Figure 3
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  		Fig. 3. After rats had been fasted for 8 h, blood glucose levels were determined immediately before glucose application (50% dextrose solution, 3 ml/kg) as well as after 15, 30, 60, 90, 120, and 240 min. The eight fasting glucose levels were not significantly different between LZRs and OZRs. Glucose intake induced postprandial hyperglycemia in all groups. OZRs exhibited higher postprandial hyperglycemia compared with LZR controls. Rosiglitazone (Rosi) treatment normalized the enhanced postprandial glucose levels in OZRs with no effect in LZRs. *P < 0.05 vs. control LZRs and control and treated OZRs; n = 6 control LZRs and OZRs and 4 treated LZRs and OZRs.

 
NADPH Oxidase Activity

The effects of rosiglitazone and tempol treatments on NADPH oxidase activity in the renal cortex are shown in Fig. 4A. Compared with LZR controls, OZRs exhibited significantly increased NADPH oxidase activity, which was normalized by rosiglitazone treatment. Tempol treatment did not significantly alter enzyme activity in either group.


Figure 4
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  		Fig. 4. A: OZRs exhibited increased NADPH oxidase activity compared with LZR controls. Rosiglitazone treatment improved the enhanced oxidase activity in OZRs with no effect in LZRs. Tempol treatment showed no significant effects on the activity of enzyme. *P < 0.05 vs. control LZRs; +P < 0.05 vs. control OZRs; n = 5 control LZRs and OZRs and 4 treated LZRs and OZRs. B: confocal images obtained using a laser scanning confocal microscopy (Leica Microsystems) from dihydroethidium-treated aortic segments (split longitudinally). Superoxide levels between control and rosiglitazone-treated LZRs and OZRs were compared. Control OZRs exhibited increased fluorescence compared with control LZRs. Rosiglitazone treatment significantly reduced the fluorescence in OZRs (treated obese) while having no effect in LZRs (treated lean). *P < 0.05 vs. control LZRs; +P < 0.01, treated vs. control OZRs; n = 4 rats/group.

 
Vascular Superoxide Levels

Figure 4B shows representative confocal images of the DHE-treated aorta from control or rosiglitazone-treated LZRs and OZRs. OZRs exhibited increased fluorescence compared with LZRs. Rosiglitazone treatment significantly reduced fluorescence in OZRs while having no effect in LZRs. Two images were obtained from each slide, and the mean value was recorded.

Effects of Rosiglitazone and Tempol Treatments on Vasodilatory Responses

Vasodilatory responses to muscle stimulation and AA administration after rosiglitazone or tempol treatments are shown in Figs. 5 and 6, respectively. Functional (Figs. 5A and 6A) and AA-induced (Figs. 5B and 6B) dilations were significantly blunted in untreated OZRs compared with LZR controls. Both rosiglitazone and tempol treatments significantly improved both vasodilatory responses to muscle stimulation and AA in OZRs with no effect in LZRs. SQ-29548 treatment had no effect on vasodilatory responses to muscle contraction or AA administration in both LZRs and treated OZRS while significantly enhancing the vasodilatory response in control OZRs.


Figure 5
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  		Fig. 5. A: OZRs exhibited significantly blunted functional vasodilation compared with LZR controls. Rosiglitazone (ROZ) treatment improved vasodilatory responses in OZRs with no effect in LZRs. SQ-29548 improved functional dilation in control OZRs while having no effect in LZRs or treated animals. *P < 0.05 vs. control LZRs; +P < 0.05 vs. control OZRs; n = 5 rats/group. B: vasodilatory responses to AA were significantly attenuated in OZRs compared with LZR controls, and rosiglitazone treatment improved vasodilatory responses. SQ-29548 administration resulted in improved AA-induced dilation in control OZRs while having no effect in LZRs or treated animals. *P < 0.05 vs. control LZRs; +P < 0.05 vs. control OZRs; n = 5 rats/group.

 

Figure 6
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  		Fig. 6. A: OZRs exhibited significantly blunted functional vasodilation compared with LZR controls. Tempol treatment improved vasodilatory responses in OZRs with no effect in LZRs. SQ-29548 improved functional dilation in control OZRs while having no effect in LZRs or treated animals. *P < 0.05 vs. control LZRs; +P < 0.05 vs. control OZRs; n = 5 rats/group. B: vasodilatory responses to AA were significantly attenuated in OZRs compared with LZR controls. Tempol treatment improved vasodilatory responses in OZRs with no effect in LZRs. SQ-29548 administration resulted in improved AA-induced dilation in control OZRs while having no effect in LZRs or treated animals. *P < 0.05 vs. control LZRs; +P < 0.05 vs. control OZRs; n = 5 rats/group.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We tested the hypothesis that insulin resistance, hyperglycemia/hyperlipidemia, and the resultant increased ROS impair functional vasodilation via increased TP-mediated vasoconstriction. The major findings in the present study are as follows: 1) the enhanced TP activation responsible for the impaired functional vasodilation in OZRs is not due to increased TXA2 or TP activity; 2) rosiglitazone treatment normalized increased insulin, triglyceride, and postprandial glucose levels as well as tNADPH oxidase activity in OZRs; 3) both rosiglitazone and tempol treatments improved vasodilatory responses in OZRs; and 4) TP inhibition with SQ-29548 improved vasodilatory responses in control OZRs with no effect in rosiglitazone- or tempol-treated animals. These findings support our hypothesis that the impaired functional dilation due to enhanced TP-mediated vasoconstriction in OZRs is related to insulin resistance and its metabolic consequences.

It has been demonstrated that the increase in blood flow in skeletal muscle during exercise is reduced in animal models (21) and humans (17) with metabolic syndrome. The mechanisms responsible for the impaired hyperemia are still unclear. Consistent with our previous study, the impaired vasodilatory responses to muscle contraction and AA in OZRs were improved following TP inhibition using SQ-29548 (Fig. 3, A and B), suggesting increased TP-mediated vasoconstriction (43). The present study shows that the in vivo vasoconstrictor response to the thromboxane analog U-46619 was not different between LZRs and OZRs (Fig. 1C), consistent with our in vitro study (37) in gracilis arteries. Thus, the enhanced TP-mediated vasoconstriction in OZRs is not due to increased TP activity or alterations in downstream signaling. Furthermore, the thromboxane synthase inhibitor 1-benzylimidazole did not alter vasodilatory responses in OZRs (Fig. 1, A and B), similar to findings in the diabetic rat (43). Therefore, the enhanced TP activation in OZRs is most likely induced by an increase in a factor(s) other than TXA2, such as PGH2. In addition, neither SQ-29548 nor 1-benzylimidazole decreased basal arteriolar diameters, suggesting that the accumulation of TP activator(s) only occurs in response to stimuli such as muscle contraction. Further studies are needed to definitely determine which factor is responsible for the enhanced TP activator(s) in OZRs during the hyperemic response.

Consistent with findings in patients and animals with metabolic syndrome, plasma insulin, triglyceride, and postprandial glucose levels were significantly higher in OZRs (Table 1 and Fig. 3), suggesting a state of insulin resistance. Although inconsistencies may exist in the observance of hyperglycemia in OZRs (40, 51), it should be reasonable that due to the insulin resistance and increased food intake, the OZR tends to "endure" longer and higher hyperglycemia. In the present study, animals had access to food from 6 PM to 6 AM, when their activity and food intake were supposed to be high (15). As a result, OZRs exhibited higher and longer postprandial hyperglycemia and elevated 24-h mean glucose levels compared with LZR controls (Fig. 2). Indeed, it has been reported that postprandial hyperglycemia, rather than impaired fasting glucose, is a risk factor for cardiovascular disease (48).

Insulin sensitizers such as rosiglitazone have become a clinically important treatment of diabetes (43). Rosiglitazone acts through the activation of intracellular peroxisome proliferator-activated receptor (PPAR)-{gamma}, resulting in an increased sensitivity of muscle and adipose tissue to insulin. In the present study, rosiglitazone treatment normalized the elevated plasma insulin, triglyceride, and postprandial glucose levels in OZRs with no effect in LZRs (Table 1 and Fig. 3), similar to results from other studies (35, 36). For example, fasting insulin and glucose levels were normalized after 2 wk of rosiglitazone treatment in 10-wk-old OZRs (51). There was an increased fatty acid (FA) uptake capacity and decline in plasma FA and triacylglycerols levels after rosiglitazone treatment with no effect on the FA transport system, implying enhanced insulin sensitivity (5, 8).

Numerous studies have suggested that both hyperlipidemia and hyperglycemia are associated with impaired vascular functions and attenuated endothelium-dependent flow-mediated vasodilation (4, 30, 31), which is improved by the administration of metformin, an insulin sensitizer (53). Hyperinsulinemia and impaired insulin-mediated vasodilation are implicated in metabolic syndrome (3, 46). Insulin may increase blood flow by stimulating endothelial NO production or through hyperpolarization of the smooth muscle cell membrane (7). However, in physiological hyperinsulinemia but otherwise normal subjects, insulin-mediated increases in plasma flow are impaired in the kidney but not altered in the leg (47), which does not support a direct effect of hyperinsulinemia on the vascular beds in skeletal muscle. A study (1) in humans suggested that insulin resistance/hyperinsulinemia is an independent predictor of decreases in endothelium-dependent vasodilation in apparently healthy individuals. Our recent study (56) showed impaired functional and AA-induced vasodilation in Type 1 diabetic rats due to enhanced TP activation and that normalization of glucose levels by insulin treatment restores vasodilatory responses. In the present study, rosiglitazone treatment improved glucose and triglyceride levels together with improved functional and AA-induced vasodilation in OZRs. Moreover, SQ-29548 only improved vasodilatory responses in nontreated OZRs with no effect in treated animals. These results suggest that the metabolic consequences of insulin resistance in OZRs are related to the altered AA metabolism and the resultant impairment in functional vasodilation.

It has been well established that insulin resistance and the resultant high glucose or triglyceride levels impair vascular function along with increased ROS (9, 12, 14, 24), and PPAR-{gamma} activation may reduce oxidative stress (2). The major mechanisms for the increased generation of endothelial ROS in obesity appear to be an increased activation of NADPH oxidase and uncoupling of endothelial NO synthase (eNOS) (31, 33). The present study showed increased superoxide levels and NADPH oxidase activity in OZRs compared with LZR controls (Fig. 4, A and B). Moreover, rosiglitazone treatment decreased superoxide, NADPH oxidase activity, and insulin resistance in OZRs along with improved vasodilatory responses, suggesting that insulin resistance and the resultant metabolic disorders impair vascular function via enhanced oxidant stress. These results were confirmed by our additional experiments showing that tempol (ROS scavenger) treatment improved functional and AA-induced dilation in OZRs (Fig. 6). Indeed, hyperglycemia and increased ROS have been shown to alter AA metabolism via nitration of prostacyclin synthase and a shunting of AA metabolism to the PGI2 precursor PGH2, resulting in reduced PGI2 production and enhanced TP activation (10, 14, 22, 61). Therefore, the incomplete restoration of vasodilatory responses in untreated OZRs by SQ-29548 may be partially due to the impaired prostacyclin synthesis (Figs. 5 and 6). A recently study (49) showed that increased endothelial sorbitol is a possible mechanism for the hyperglycemia-induced ROS and the resultant enhanced TP activation, resulting in impaired flow-mediated dilation. In addition, rosiglitazone treatment decreased NADPH oxidase activity but failed to complete restore superoxide levels, suggesting the possibility of other NADPH oxidase-independent ROS, which may account for the remained impairment in functional dilation after treatment in OZRs. However, the underlying mechanism(s) responsible for the ROS-induced impairment in AA metabolism still needs to be determined.

In addition to accelerated insulin secretion and glucose uptake, PPAR activation may also have other beneficial effects such as decreasing inflammation (6, 11, 26). Due to the coexistence of insulin resistance, inflammation, and increased ROS in metabolic syndrome, it is hard to conclude the beneficial effects exclusively from insulin sensitization on vascular function since improvement in one will result in alterations in others. For example, insulin resistance and hyperglycemia/hyperlipidemia can increase inflammatory responses (39), whereas inflammatory cytokines such as TNF-{alpha} and leptin may, in turn, induce the insulin resistance (42) and endothelial dysfunction (26). These findings complicate the explanation of the beneficial effects that resulted from rosiglitazone treatment in the present study. In addition, rosiglitazone might directly affect vascular function despite the improved insulin resistance. For example, direct exposure to arterioles to rosiglitazone leads to a vasoconstrictor response (54) and increased endothelial permeability (27). However, in the present study, basal diameter, functional and AA-induced dilations, and adenosine-induced dilations were not altered in treated LZRs, suggesting that 2 wk of treatment with rosiglitazone does not have nonspecific effects on vascular tone.

In the present study, rosiglitazone treatment failed to normalize functional vasodilation in OZRs (Figs. 5 and 6), suggesting that some other factor(s) may be also involved in the impaired vasodilatory responses. Frisbee (18, 20) demonstrated enhanced {alpha}-adrenergic constriction of arterioles in OZRs, which contributes to impaired dilator responses and reduced muscle blood flow. Although hypertension has been recognized as a risk factor for vascular dysfunction in metabolic syndrome, the development of hypertension in OZRs remains unclear. For example, our previous study (58) showed that mean blood pressures (BP) were not different between 12-wk-old LZRs and OZRs, similar to findings from others (19, 42, 52). Wallis et al. (55) showed that BPs are not different between LZRs and OZRs even at the age of 20 wk old. In contrast, other studies (29, 41) have reported that BPs are higher in 12-wk-old OZRs than in LZR controls, with the hypertension attenuated by rosiglitazone treatment (29). However, we would suggest that these mild increases in BP exhibited in OZRs (29, 41) and the short period of "hypertension" do not likely contribute to the severe impairment in AA metabolism and functional vasodilation. Indeed, a recent study (45) in OZRs showed that insulin resistance-mediated stimulation of the sympathetic nervous system is related to altered glucose metabolism before the onset of hypertension.

In summary, restoration of insulin resistance and blood plasma glucose and triglyceride levels with rosiglitazone treatment improved superoxide and NADPH oxidase activity and functional and AA-induced vasodilation in OZRs along with an attenuation of TP-mediated vasoconstriction. Tempol-treated OZRs exhibited increased vasodilatory responses to muscle stimulation and AA due to attenuated TP-mediated vasoconstriction. These results suggest that, in OZRs, insulin resistance, hyperglycemia/hyperlipidemia, and the resultant ROS impair functional vasodilation via increased TP-mediated vasoconstriction. Further studies are needed to determine the contributions of increased inflammatory responses and oxidant stress to the impaired AA metabolism in this metabolic syndrome model.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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REFERENCES
 
This work was supported by National Heart, Lung, and Blood Institute Grant HL-51971 and HL-63958 and by an American Heart Association Southeastern Affiliate postdoctoral fellowship.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Robert Hester, Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, 2500 North State St., Jackson, MI 39216-4505 (e-mail: rhester{at}physiology.umsmed.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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  1. Ardigo D, Franzini L, Valtuena S, Monti LD, Reaven GM, Zavaroni I. Relation of plasma insulin levels to forearm flow-mediated dilatation in healthy volunteers. Am J Cardiol 97: 1250–1254, 2006.[CrossRef][Web of Science][Medline]
  2. Bagi Z, Koller A, Kaley G. PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. Am J Physiol Heart Circ Physiol 286: H742–H748, 2004.[Abstract/Free Full Text]
  3. Baron AD. Insulin resistance and vascular function. J Diabetes Complications 16: 92–102, 2002.[CrossRef][Web of Science][Medline]
  4. Beckman JA, Goldfine AB, Gordon MB, Creager MA. Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 103: 1618–1623, 2001.[Abstract/Free Full Text]
  5. Bennett SM, Agrawal A, Elasha H, Heise M, Jones NP, Walker M, Wilding JP. Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance. Diabet Med 21: 415–422, 2004.[CrossRef][Web of Science][Medline]
  6. Clark RB. The role of PPARs in inflammation and immunity. J Leukoc Biol 71: 388–400, 2002.[Abstract/Free Full Text]
  7. Cleland SJ, Petrie JR, Ueda S, Elliott HL, Connell JM. Insulin as a vascular hormone: implications for the pathophysiology of cardiovascular disease. Clin Exp Pharmacol Physiol 25: 175–184, 1998.[Web of Science][Medline]
  8. Coort SL, Coumans WA, Bonen A, van der Vusse GJ, Glatz JF, Luiken JJ. Divergent effects of rosiglitazone on protein-mediated fatty acid uptake in adipose and in muscle tissues of Zucker rats. J Lipid Res 46: 1295–1302, 2005.[Abstract/Free Full Text]
  9. Cosentino F, Luscher TF. Endothelial dysfunction in diabetes mellitus. J Cardiovasc Pharmacol 32, Suppl 3: S54–S61, 1998.[Web of Science][Medline]
  10. Cosentino F, Eto M, De Paolis P, van der LB, Bachschmid M, Ullrich V, Kouroedov A, Delli GC, Joch H, Volpe M, Luscher TF. High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation 107: 1017–1023, 2003.[Abstract/Free Full Text]
  11. Cuzzocrea S, Pisano B, Dugo L, Ianaro A, Maffia P, Patel NS, Di Paola R, Ialenti A, Genovese T, Chatterjee PK, Di Rosa M, Caputi AP, Thiemermann C. Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. Eur J Pharmacol 483: 79–93, 2004.[CrossRef][Web of Science][Medline]
  12. Dai FX, Diederich A, Skopec J, Diederich D. Diabetes-induced endothelial dysfunction in streptozotocin-treated rats: role of prostaglandin endoperoxides and free radicals. J Am Soc Nephrol 4: 1327–1336, 1993.[Abstract]
  13. Davi G, Guagnano MT, Ciabattoni G, Basili S, Falco A, Marinopiccoli M, Nutini M, Sensi S, Patrono C. Platelet activation in obese women: role of inflammation and oxidant stress. JAMA 288: 2008–2014, 2002.[Abstract/Free Full Text]
  14. Du X, Edelstein D, Obici S, Higham N, Zou MH, Brownlee M. Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest 116: 1071–1080, 2006.[CrossRef][Web of Science][Medline]
  15. Evans HL. Rats' activity: influence of light-dark cycle, food presentation and deprivation. Physiol Behav 7: 455–459, 1971.[CrossRef][Medline]
  16. Fortepiani LA, Reckelhoff JF. Increasing oxidative stress with molsidomine increases blood pressure in genetically hypertensive rats but not normotensive controls. Am J Physiol Regul Integr Comp Physiol 289: R763–R770, 2005.[Abstract/Free Full Text]
  17. Fossum E, Hoieggen A, Moan A, Rostrup M, Nordby G, Kjeldsen SE. Relationship between insulin sensitivity and maximal forearm blood flow in young men. Hypertension 32: 838–843, 1998.[Abstract/Free Full Text]
  18. Frisbee JC. Vascular adrenergic tone and structural narrowing constrain reactive hyperemia in skeletal muscle of obese Zucker rats. Am J Physiol Heart Circ Physiol 290: H2066–H2074, 2006.[Abstract/Free Full Text]
  19. Frisbee JC. Hypertension-independent microvascular rarefaction in the obese Zucker rat model of the metabolic syndrome. Microcirculation 12: 383–392, 2005.[CrossRef][Web of Science][Medline]
  20. Frisbee JC. Enhanced arteriolar alpha-adrenergic constriction impairs dilator responses and skeletal muscle perfusion in obese Zucker rats. J Appl Physiol 97: 764–772, 2004.[Abstract/Free Full Text]
  21. Frisbee JC. Impaired skeletal muscle perfusion in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 285: R1124–R1134, 2003.[Abstract/Free Full Text]
  22. Frisbee JC. Impaired dilation of skeletal muscle microvessels to reduced oxygen tension in diabetic obese Zucker rats. Am J Physiol Heart Circ Physiol 281: H1568–H1574, 2001.[Abstract/Free Full Text]
  23. Frisbee JC. Impaired dilation of skeletal muscle microvessels to reduced oxygen tension in diabetic obese Zucker rats. Am J Physiol Heart Circ Physiol 281: H1568–H1574, 2001.[Abstract/Free Full Text]
  24. Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 19: 257–267, 1996.[Abstract]
  25. Hester RL, Choi J. Blood flow control during exercise: role for the venular endothelium? Exerc Sport Sci Rev 30: 147–151, 2002.[CrossRef][Web of Science][Medline]
  26. Hetzel J, Balletshofer B, Rittig K, Walcher D, Kratzer W, Hombach V, Haring HU, Koenig W, Marx N. Rapid effects of rosiglitazone treatment on endothelial function and inflammatory biomarkers. Arterioscler Thromb Vasc Biol 25: 1804–1809, 2005.[Abstract/Free Full Text]
  27. Idris I, Gray S, Donnelly R. Rosiglitazone and pulmonary oedema: an acute dose-dependent effect on human endothelial cell permeability. Diabetologia 46: 288–290, 2003.[Web of Science][Medline]
  28. Ishizuka T, Matsui T, Kurita A. Ramatroban, a TP receptor antagonist, improves vascular responses to acetylcholine in hypercholesterolemic rabbits in vivo. Eur J Pharmacol 468: 27–35, 2003.[CrossRef][Web of Science][Medline]
  29. Khan O, Riazi S, Hu X, Song J, Wade JB, Ecelbarger CA. Regulation of the renal thiazide-sensitive Na-Cl cotransporter, blood pressure, and natriuresis in obese Zucker rats treated with rosiglitazone. Am J Physiol Renal Physiol 289: F442–F450, 2005.[Abstract/Free Full Text]
  30. Kim SH, Park KW, Kim YS, Oh S, Chae IH, Kim HS, Kim CH. Effects of acute hyperglycemia on endothelium-dependent vasodilation in patients with diabetes mellitus or impaired glucose metabolism. Endothelium 10: 65–70, 2003.[CrossRef][Web of Science][Medline]
  31. Komers R, Zdychova J, Cahova M, Kazdova L, Lindsley JN, Anderson S. Renal cyclooxygenase-2 in obese Zucker (fatty) rats. Kidney Int 67: 2151–2158, 2005.[CrossRef][Web of Science][Medline]
  32. Kraml P, Syrovatka P, Stipek S, Fialova L, Koprivova H, Potockova J, Andel M. Hyperlipoproteinemia impairs endothelium-dependent vasodilation. Physiol Res 53: 471–480, 2004.[Web of Science][Medline]
  33. Kuklinska AM, Musial WJ, Kaminski KA, Kralisz P, Modrzejewski W, Sobkowicz B, Dobrzycki S, Stec S, Wojtkowska I. Low dose rofecoxib, inflammation and prostacyclin synthesis in acute coronarysyndromes. Rocz Akad Med Bialymst 50: 339–342, 2005.[Medline]
  34. Lash JM, Bohlen HG. Perivascular and tissue PO2 in contracting rat spinotrapezius muscle. Am J Physiol Heart Circ Physiol 252: H1192–H1202, 1987.[Abstract/Free Full Text]
  35. Minoura H, Takeshita S, Yamamoto T, Mabuchi M, Hirosumi J, Takakura S, Kawamura I, Seki J, Manda T, Ita M, Mutoh S. Ameliorating effect of FK614, a novel nonthiazolidinedione peroxisome proliferator-activated receptor gamma agonist, on insulin resistance in Zucker fatty rat. Eur J Pharmacol 519: 182–190, 2005.[CrossRef][Web of Science][Medline]
  36. Muurling M, Mensink RP, Pijl H, Romijn JA, Havekes LM, Voshol PJ. Rosiglitazone improves muscle insulin sensitivity, irrespective of increased triglyceride content, in ob/ob mice. Metabolism 52: 1078–1083, 2003.[CrossRef][Web of Science][Medline]
  37. Naik JS, Xiang L, Hester RL. Enhanced role for RhoA-associated kinase in adrenergic-mediated vasoconstriction in gracilis arteries from obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 290: R154–R161, 2006.[Abstract/Free Full Text]
  38. Nuttle LC, Ligon AL, Farrell KR, Hester RL. Inhibition of phospholipase A2 attenuates functional hyperemia in the hamster cremaster muscle. Am J Physiol Heart Circ Physiol 276: H1289–H1294, 1999.[Abstract/Free Full Text]
  39. O'Keefe JH, Bell DS. Postprandial hyperglycemia/hyperlipidemia (postprandial dysmetabolism) is a cardiovascular risk factor. Am J Cardiol 100: 899–904, 2007.[CrossRef][Web of Science][Medline]
  40. Oltman CL, Richou LL, Davidson EP, Coppey LJ, Lund DD, Yorek MA. Progression of coronary and mesenteric vascular dysfunction in Zucker obese and Zucker diabetic fatty rats. Am J Physiol Heart Circ Physiol 291: H1780–H1787, 2006.[Abstract/Free Full Text]
  41. Overton JM, Williams TD, Chambers JB, Rashotte ME. Cardiovascular and metabolic responses to fasting and thermoneutrality are conserved in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 280: R1007–R1015, 2001.[Abstract/Free Full Text]
  42. Pamidimukkala J, Jandhyala BS. Effects of salt rich diet in the obese Zucker rats: studies on renal function during isotonic volume expansion. Clin Exp Hypertens 26: 55–67, 2004.[CrossRef][Web of Science][Medline]
  43. Quilley J, McGiff JC. Renal vascular responsiveness to arachidonic acid in experimental diabetes. Br J Pharmacol 100: 336–340, 1990.[Web of Science][Medline]
  44. Raskin P, Rappaport EB, Cole ST, Yan Y, Patwardhan R, Freed MI. Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with type II diabetes. Diabetologia 43: 278–284, 2000.[CrossRef][Web of Science][Medline]
  45. Ruggeri P, Brunori A, Cogo CE, Storace D, Di Nardo F, Burattini R. Enhanced sympathetic reactivity associates with insulin resistance in the young Zucker rat. Am J Physiol Regul Integr Comp Physiol 291: R376–R382, 2006.[Abstract/Free Full Text]
  46. Shinozaki K, Kashiwagi A, Masada M, Okamura T. Molecular mechanisms of impaired endothelial function associated with insulin resistance. Curr Drug Targets Cardiovasc Haematol Disord 4: 1–11, 2004.[Medline]
  47. Ter Maaten JC, Bakker SJ, Serne EH, Moshage HJ, Donker AJ, Gans RO. Insulin-mediated increases in renal plasma flow are impaired in insulin-resistant normal subjects. Eur J Clin Invest 30: 1090–1098, 2000.[CrossRef][Web of Science][Medline]
  48. Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Funagata Diabetes Study. Diabetes Care 22: 920–924, 1999.[Abstract]
  49. Toth E, Racz A, Toth J, Kaminski PM, Wolin MS, Bagi Z, Koller A. Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, diminished NO and enhanced PGH2/TXA2 mediation. Am J Physiol Heart Circ Physiol 293: H3096–H3104, 2007.[Abstract/Free Full Text]
  50. Traupe T, Lang M, Goettsch W, Munter K, Morawietz H, Vetter W, Barton M. Obesity increases prostanoid-mediated vasoconstriction and vascular thromboxane receptor gene expression. J Hypertens 20: 2239–2245, 2002.[CrossRef][Web of Science][Medline]
  51. Trivedi M, Lokhandwala MF. Rosiglitazone restores renal D1A receptor-Gs protein coupling by reducing receptor hyperphosphorylation in obese rats. Am J Physiol Renal Physiol 289: F298–F304, 2005.[Abstract/Free Full Text]
  52. Verma S, Leung YM, Yao L, Battell M, Dumont AS, McNeill JH. Hyperinsulinemia superimposed on insulin resistance does not elevate blood pressure. Am J Hypertens 14: 429–432, 2001.[CrossRef][Web of Science][Medline]
  53. Vitale C, Mercuro G, Cornoldi A, Fini M, Volterrani M, Rosano GM. Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med 258: 250–256, 2005.[CrossRef][Web of Science][Medline]
  54. Walker AB, Naderali EK, Chattington PD, Buckingham RE, Williams G. Differential vasoactive effects of the insulin sensitizers rosiglitazone (BRL 49653) and troglitazone on human small arteries in vitro. Diabetes 47: 810–814, 1998.[Abstract]
  55. Wallis MG, Wheatley CM, Rattigan S, Barrett EJ, Clark AD, Clark MG. Insulin-mediated hemodynamic changes are impaired in muscle of Zucker obese rats. Diabetes 51: 3492–3498, 2002.[Abstract/Free Full Text]
  56. Xiang L, Naik JS, Abram SR, Hester RL. Chronic hyperglycemia impairs functional vasodilation via increasing thromboxane receptor-mediated vasoconstriction. Am J Physiol Heart Circ Physiol 292: H231–H236, 2007.[Abstract/Free Full Text]
  57. Xiang L, Naik JS, Hodnett BL, Hester RL. Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 290: R134–R138, 2006.[Abstract/Free Full Text]
  58. Xiang L, Naik J, Hester RL. Exercise-induced increase in skeletal muscle vasodilatory responses in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 288: R987–R991, 2005.[Abstract/Free Full Text]
  59. Xu H, Fink GD, Galligan JJ. Tempol lowers blood pressure and sympathetic nerve activity but not vascular O2– in DOCA-salt rats. Hypertension 43: 329–334, 2004.[Abstract/Free Full Text]
  60. Yamada M, Omata K, Abe F, Ito S, Abe K. Changes in prostacyclin, thromboxane A2 and F2-isoprostanes, and influence of eicosapentaenoic acid and antiplatelet agents in patients with hypertension and hyperlipidemia. Immunopharmacology 44: 193–198, 1999.[CrossRef][Web of Science][Medline]
  61. Zou MH, Shi C, Cohen RA. High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H2 receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes 51: 198–203, 2002.[Abstract/Free Full Text]



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