The aim of this study was to investigate the antihypertensive activity of the ethanol extract (EE) of red mold rice (RMR) and to explore its mechanism of action. In comparison to EE of nonfermented rice, the EE of RMR contained higher levels of total phenolic, total flavonoids, gamma-aminobutyric acid, and monacolin K. Intravenous bolus administration of the EE (10-50 mg/kg) resulted in biphasic, dose-dependent antihypertensive effects and decreases in heart rate, cardiac contractility, and sympathetic vasomotor tone in spontaneously hypertensive rats. The initial and delayed antihypertensive responses, and the negative inotropic and chronotropic effects of EE treatment (30 mg/kg, iv.) were significantly reduced by pretreatment with hexamethonium (30 mg/kg, i.v.) and N-G-nitro-L-arginine methyl ester (20 mg/kg, i.v.). Pretreatment with methylatropine (1 mg/kg, i.v.), however, reversed the initial but not the delayed bradycardiac and negative inotropic effects of EE. We conclude that systemic administration of the EE of RMR elicited both transient and delayed antihypertensive actions that were mediated by the withdrawal of sympathetic tone and the production of nitric oxide (NO). The negative inotropic and chronotropic effects of EE may result from a direct sympathetic inhibition of the heart as well as an activation of the NO-dependent pathway.