Lusha Xiang

Insulin resistance and impaired functional vasodilation in obese Zucker rats.

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 muM) in the absence and presence of the TP antagonist SQ-29548 (1 muM). 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.

KATP-mediated Vasodilation is Impaired in Obese Zucker Rats

Objective: Skeletal muscle blood flow during exercise is impaired in obesity. We tested the hypothesis that the attenuated vasodilation in skeletal muscle arterioles of obese Zucker rats (OZR) is due to altered KATP channel‐mediated vasodilation.

Functional vasodilation in the rat spinotrapezius muscle: role of nitric oxide, prostanoids and epoxyeicosatrienoic acids.

1 The present study was designed to determine the mechanisms responsible for functional vasodilation of arterioles paired and unpaired with venules in the rat spinotrapezius muscle. 2 The spinotrapezius muscle (from Sprague‐Dawley rats) was treated with combinations of the nitric oxide synthase inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME; 100 mmol/L), the cyclo‐oxygenase inhibitor indomethacin (10 mmol/L) and the epoxygenase inhibitor 6‐(2‐propargyloxyphenyl) hexanoic acid (PPOH; 30 mmol/L) to determine vascular responses to muscle stimulation. Both paired and unpaired arcade arterioles were chosen for microcirculatory observation. Arteriolar diameter was measured following 2 min muscle stimulation before and 30 min after subsequent application of each inhibitor. 3 In all cases, l‐NAME treatment resulted in decreased basal diameter that was restored to control levels by the addition of sodium nitroprusside (0.01–0.1 mmol/L) to the superfusion solution. NG‐Nitro‐l‐arginine methyl ester significantly inhibited the functional dilation in both paired (–20 ± 3%) and unpaired (–29 ± 3%) arterioles, whereas these inhibitory effects of l‐NAME were diminished after pretreatment with indomethacin and PPOH. Indomethacin treatment attenuated the dilation in paired (–33 ± 5%) but not unpaired (–6 ± 4%) arterioles. Treatment with PPOH had no effect on the functional dilation in either set of arterioles. Approximately 50% of the vasodilatory responses remained in the presence of l‐NAME, indomethacin and PPOH. 4 These results suggest that both nitric oxide and vasodilator prostanoid(s) are involved in mediating functional vasodilation in the rat spinotrapezius. The vasodilator prostanoid(s) released from venules is responsible for a portion of the vasodilation of the paired arteriole. The results also suggest possible interactions between the synthesis of nitric oxide and prostaglandin or epoxyeicosatrienoic acids during muscle contraction.

Inhibition of NADPH oxidase prevents acute lung injury in obese rats following severe trauma.

Lung capillary filtration coefficient (Kf) and impacts of oxidative stress have not been determined in the setting of severe trauma, especially in obese patients who exhibit increased lung injury. We hypothesized that severe trauma leads to a greater increase in lung Kf in obesity due to exacerbated production of and/or vulnerability to oxidative stress. Severe trauma was induced in lean and obese Zucker rats by muscle injury, fibula fracture, and bone component injection to both hindlimbs, with or without 24-h treatments of apocynin, a NADPH oxidase (NOX) inhibitor. Lung wet/dry weight ratios, lung vascular Kf, lung neutrophil counts, lung NOX and myeloperoxidase (MPO) activity, and plasma IL-6 levels were measured 24 h after trauma. In an additional study, lungs were isolated from nontrauma lean and obese rats to determine the acute effect of phenazime methosulfate, a superoxide donor, on pulmonary vascular Kf. After trauma, compared with lean rats, obese rats exhibited greater increases in lung capillary Kf, neutrophil accumulation, NOX and MPO activity, and plasma IL-6. The lung wet/dry weight ratio was increased in obese rats but not in lean rats. Apocynin treatment decreased lung Kf, neutrophil counts, NOX and MPO activities, wet/dry weight ratio, and plasma IL-6 in obese rats. Phenazime methosulfate treatment resulted in a greater increase in lung Kf in nontrauma obese rats compared with nontrauma lean rats. These results suggest that obese rats are susceptible to lung injury following severe trauma due to increased production of and responsiveness to pulmonary oxidative stress.

β2-Adrenoreceptor blockade improves early posttrauma hyperglycemia and pulmonary injury in obese rats

Early hyperglycemia after trauma increases morbidity and mortality. Insulin is widely used to control posttrauma glucose, but this treatment increases the risk of hypoglycemia. We tested a novel method for early posttrauma hyperglycemia control by suppressing hepatic glycogenolysis via β2-adrenoreceptor blockade [ICI-118551 (ICI)]. We have shown that, after severe trauma, obese Zucker (OZ) rats, similar to obese patients, exhibit increased acute lung injury compared with lean Zucker (LZ) rats. We hypothesized that OZ rats exhibit a greater increase in early posttrauma glucose compared with LZ rats, with the increased posttrauma hyperglycemia suppressed by ICI treatment. Orthopedic trauma was applied to both hindlimbs in LZ and OZ rats. Fasting plasma glucose was then monitored for 6 h with or without ICI (0.2 mg·kg(-1)·h(-1) iv.) treatment. One day after trauma, plasma IL-6 levels, lung neutrophil numbers, myeloperoxidase (MPO) activity, and wet-to-dry weight ratios were measured. Trauma induced rapid hepatic glycogenolysis, as evidenced by decreased liver glycogen levels, and this was inhibited by ICI treatment. Compared with LZ rats, OZ rats exhibited higher posttrauma glucose, IL-6, lung neutrophil infiltration, and MPO activity. Lung wet-to-dry weight ratios were increased in OZ rats but not in LZ rats. ICI treatment reduced the early hyperglycemia, lung neutrophil retention, MPO activity, and wet-to-dry weight ratio in OZ rats to levels comparable with those seen in LZ rats, with no effect on blood pressure or heart rate. These results demonstrate that β2-adrenoreceptor blockade effectively reduces the early posttrauma hyperglycemia, which is associated with decreased lung injury in OZ rats.

Impaired blood pressure compensation following hemorrhage in conscious obese Zucker rats

AIMS Hemorrhagic shock leads to a higher risk of mortality and morbidity in obese patients, however the mechanisms for these outcomes are unclear. We hypothesized that following severe hemorrhage, blood pressure control in conscious obese Zucker rats (OZ) is impaired. MAIN METHODS Experiments were performed in conscious lean Zucker rats (LZ) and OZ. Blood pressure, heart rate, cardiac output, total peripheral resistance (TPR), plasma renin activity (PRA), plasma antidiuretic hormone (ADH), and blood gasses were measured before and after severe hemorrhage (35% of the total blood volume). KEY FINDINGS Basal blood pressure, cardiac output, TPR, PRA, and ADH levels were not different between LZ and OZ. Compared to LZ, OZ exhibited impaired baroreflex control of heart rate and showed higher levels of vascular adrenergic tone. One hour after the hemorrhage, LZ and OZ exhibited similar decreases in cardiac output. However, blood pressure, heart rate, TPR, PRA, and ADH levels were lower in OZ than in LZ. SIGNIFICANCE These results indicate that conscious OZ has impaired blood pressure compensation after hemorrhage due to a blunted increase in TPR. This is due at least in part to an impaired regulation of vasoconstrictor hormones. To our knowledge, the current study is the first to demonstrate that hemodynamic responses and associated hormone secretion are impaired in a conscious obese model.

Improved functional vasodilation in obese Zucker rats following exercise training

Obese individuals exhibit impaired functional vasodilation and exercise performance. We have demonstrated in obese Zucker rats (OZ), a model of morbid obesity, that insulin resistance impairs functional vasodilation via an increased thromboxane receptor (TP)-mediated vasoconstriction. Chronic treadmill exercise training improves functional vasodilation in the spinotrapezius muscle of the OZ, but the mechanisms responsible for the improvement in functional vasodilation are not clear. Based on evidence that exercise training improves insulin resistance, we hypothesized that, in the OZ, exercise training increases functional vasodilation and exercise capability due to decreases TP-mediated vasoconstriction associated with improved insulin sensitivity. Six-week-old lean Zucker rats (LZ) and OZ were exercised on a treadmill (24 m/min, 30 min/day, 5 days/wk) for 6 wk. An oral glucose tolerance test was performed at the end of the training period. We measured functional vasodilation in both exercise trained (spinotrapezius) and nonexercise trained (cremaster) muscles to determine whether the improved functional vasodilation following exercise training in OZ is due to a systemic improved insulin resistance. Compared with LZ, the sedentary OZ exhibited impairments in glucose tolerance and functional vasodilation in both muscles. The TP antagonist SQ-29548 improved the vasodilator responses in the sedentary OZ with no effect in the LZ. Exercising training of the LZ increased the functional vasodilation in spinotrapezius muscle, with no effect in the cremaster muscle. Exercising training of the OZ improved glucose tolerance, along with increased functional vasodilation, in both the spinotrapezius and cremaster muscles. SQ-29548 treatment had no effect on the vasodilator responses in either cremaster or spinotrapezius muscles of the exercise-trained OZ. These results suggest that, in the OZ, there is a global effect of exercising training to improve insulin resistance and increase functional vasodilation via a decreased TP-mediated vasoconstriction.

Impaired vascular KATP function attenuates exercise capacity in obese zucker rats.

Obese subjects exhibit decreased exercise capacity (VO2max). We have shown that vascular KATP channel mediates arteriolar dilation to muscle contraction. We hypothesize that exercise capacity is decreased in obesity due to impaired vascular KATP function.

Orthopedic trauma-induced pulmonary injury in the obese Zucker rat.

Please cite this paper as: Xiang, Hester, Fuller, Sebai, Mittwede, Jones, Aneja and Russell (2010). Orthopedic Trauma‐Induced Pulmonary Injury in the Obese Zucker Rats. Microcirculation17(8), 650–659.

Oxidative stress increases pulmonary vascular permeability in diabetic rats through activation of transient receptor potential melastatin 2 channels.

In vitro superoxide activates pulmonary endothelial TRPM2 channels and increases Kf. We hypothesized that pulmonary capillary Kf is increased in a model of type I diabetes due to elevated vascular superoxide and resultant TRPM2 channel activation.