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Background: Xenophyllum poposum is an endemic species of the Andes Cordillera, popularly known as Popusa. Popusa is widely used by mountain communities as a folk medicine to treat altitude sickness and hypertension., Purpose: The aim of this study is to evaluate the hypotensive effects and vascular reactivity of Popusa extracts and its pure isolated compounds., Methods: Hydroalcoholic extract of Xenophyllum poposum (HAE X. poposum; 40 mg/kg dose) were administered to rats by gavage and mean arterial pressures were recorded. Organ bath studies were conducted in endothelium-intact and denuded rings, and the vascular reactivity of the HAE X. poposum extract and its isolated compounds were compared and analysed. Cytosolic Ca 2+ was measured in vascular smooth muscle cell line A7r5 using Fura2-AM., Results: HAE X. poposum significantly reduced the mean arterial blood pressure and heart rate in normotensive rats chronically treated with the extract, as well as mice acutely treated with the extract. A negative chronotropic effect was observed in the isolated rat heart. HAE X. poposum induced endothelial vasodilation mediated by nitric oxide (NO), reduced the contractile response to PE, and decreased PE-induced intracellular Ca 2+ influx in vascular smooth muscle cells. Pure compounds isolated from HAE X. poposum such as 4‑hydroxy‑3-(3-methyl-2-butenyl) acetophenone, 5-acetyl-6‑hydroxy‑2-isopropenyl-2, and 3-dihydrobenzofurane (dihydroeuparin) also triggered endothelium-dependent vasodilation., Conclusion: HAE X. poposum decreases blood pressure, heart rate and vascular response. The vasodilation properties of HAE X. poposum extract and its isolated compounds may act through the endothelial nitric oxide synthase, as well as calcium channel blocker mechanisms. The results of the present study provide the first qualitative analysis that supports the use of X. poposum in traditional folk medicine for the treatment of altitude sickness and hypertension., (Copyright © 2018. Published by Elsevier GmbH.)