Objective: Normal perivascular adipose tissue secretes an adipocyte-derived relaxing factor (ADRF) that relaxes small systemic resistance-arteries by opening KCNQ potassium channels. The anti-contractile effects of perivascular fat are diminished in spontaneously hypertensive (SHR) rats and New Zealand obese (NZO) mice. We tested the hypothesis that pharmacological opening of KCNQ channels improves the paracrine vasorelaxation by perivascular fat and reduces systemic arterial blood pressure in these models of systemic arterial hypertension. Methods: We used the KCNQ channel openers retigabine, VRX0530727, VRX0621238, and VRX0621688, and performed isometric contraction studies on systemic arteries and arterial blood pressure measurements. Results: In extension of published findings, we found a prominent anti-contractile effect of perivascular fat also in rat skeletal muscle (gracilis) arteries that is mediated by KCNQ channels. In gracilis arteries of SHR, KCNQ channel openers improved the diminished anti-contractile effects of perivascular fat. Similar effects were observed in mesenteric arteries of NZO mice. Retigabine and VRX0621688 (9 mg/kg i.p. each) reduced arterial blood pressure in SHR rats. VRX0621688 (15 mg/kg i.p.) reduced blood pressure in NZO mice and C57BL/6J mice. Retigabine and VRX0530727 were less effective. Conclusion: We conclude that KCNQ channel opening is an effective mechanism to improve vascular dysfunction by diminished paracrine control of perivascular fat and represents a novel approach to treat systemic arterial hypertension, with increased high impact in obesity hypertension.