Motivation: We investigated the effects of a chronic anti-hypertensive treatment using centrally-acting sympatho-inhibitory drugs on microvascular parameters in a rat model of metabolic syndrome (MS) induced by long-term high-fat diet with salt supplementation. Methods: Fifty male adult Wistar rats were used in conformity with the guidelines of the Animals Care and Use Comitee of the Oswaldo Cruz Foundation, Brazil (Autorization P 31-11). They were maintained under normal (CON, n = 10) or high-fat diet (HFD, n = 40) during 20 weeks. Thereafter, the HFD group received oral clonidine (HFD-CLO, 0.1 mg/kg), rilmenidine (HFD-RIL, 1 mg/kg), LNP 599 (HFD-LNP, 10 mg/kg) or vehicle (HFD-CON). Functional capillary density (FCD) was evaluated in the gracilis muscle and skin of the ear using intravital videomicroscopy and structural capillary density (SCD) was studied in the skeletal muscle and left ventricle using histochemical analysis. Systolic blood pressure was evaluated by photo-plethysmography and plasma catecholamines by HPLC determination. Plasma glucose, triglycerides and cholesterol were determined by enzymatic assays. Results: There was an increase in systolic blood pressure (178±2 vs. 138±3 mmHg, P<0.05) and heart rate (412±8 vs. 336±5 bpm, P<0.05) in the HFD-CON compared to the CON group. The HFD-CON group also presented a decrease in FCD and SCD in the gracilis muscle, compared to CON group (153±8 vs. 253±16 capillaries/mm2 and 1.5±0.08 vs. 1.8±0.04 capillaries/fiber, P<0.05, respectively). However, there were no alterations in FCD in the skin. The SCD was reduced in the left ventricle of the HFD-CON group when compared to the CON group (0.18±0.01 vs. 0.33±0.01 Vv[cap]/Vv[fib], P<0.05). The groups of animals submitted to HFD and treated with clonidine, rilmenidine and LNP 599 presented a similar reduction in systolic blood pressure (155±4, 161±4 and 156±4 mmHg, respectively, P<0.05) when compared to the HFD-CON group (178±2 mmHg) and in adrenaline levels (68±7 and 64±8 and 64±8 pg/mL, respectively, P<0.05) when compared to the HFD-CON group (89±4 pg/mL). These reductions in systemic catecholamines were accompanied by an increase in the FCD and SCD in the skeletal muscle when compared to the HFD-CON group. Moreover, there was an increase in the SCD in the left ventricle in the HFD-RIL group when compared to the HFD-CON group. Conclusions: The modulation of sympathetic activity using chronic anti-hypertensive treatment with centrally-acting drugs results in a simultaneous reduction of arterial pressure and plasma catecholamines accompanied by an improvement of capillary rarefaction in the skeletal muscle and left ventricle in an experimental model of MS in rats.