sq-29548 and Hyperlipidemias

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.

Topics: Animals; Antioxidants; Arachidonic Acid; Arterioles; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Cyclic N-Oxides; Disease Models, Animal; Electric Stimulation; Fatty Acids, Unsaturated; Hydrazines; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Insulin; Insulin Resistance; Kidney Cortex; Male; Muscle, Skeletal; NADPH Oxidases; Obesity; Oxidative Stress; Rats; Rats, Zucker; Receptors, Thromboxane; Rosiglitazone; Spin Labels; Superoxides; Thiazolidinediones; Thromboxanes; Time Factors; Triglycerides; Vasoconstriction; Vasodilation