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Obesity frequently leads to the development of hypertension. We hypothesized that high-fat diet (HFD)-induced obesity impairs the endothelium-dependent dilation of arterioles. Male Wistar rats were fed with normal (control) or HFD (60% of saturated fat, for 10 wk). In rats with HFD, body weight, mean arterial blood pressure, and serum insulin, cholesterol, and glucose were elevated. In isolated gracilis muscle arterioles (diameter: ∼160 μm) of HFD, rat dilations to ACh (at 1 μM, maximum: 83 ± 3%) and histamine (at 10 μM, maximum: 16 ± 4%) were significantly (P < 0.05) decreased compared with those of control responses (maximum: 90 ± 2 and 46 ± 4%, respectively). Dilations to the NO donor sodium nitroprusside were similar in the two groups. Inhibition of NO synthesis by N^ω-nitro-l-arginine methyl ester reduced ACh- and histamine-induced dilations in control arterioles but had no effect on microvessels of HFD …