Prazosin or doxazosin, selective alpha 1-adrenergic receptor inhibitors used in the treatment of hypertension, are known from clinical studies to lower plasma lipids. When diets and dosing regimens are carefully controlled, both agents produce similar effects on plasma lipids in rats, i.e., decreases in triglycerides and in the non-high density lipoprotein (non-HDL) fraction of cholesterol. In order to conduct these studies, models of rats partially fasting (PF) and eating a high-sucrose diet were developed. The effects of prazosin 2.3 mg/kg/day and doxazosin 20 mg/kg/day on plasma levels of triglycerides, total and HDL cholesterol, free fatty acids (FFA), ketones, and other metabolites were measured in rats in the fed, fasting, or PF states, at various times after a meal, and with a high-cholesterol diet. The pattern of responses leads to the hypothesis that, under conditions of partial or complete fasting, alpha 1-adrenergic receptor inhibition can alter intrahepatic FFA metabolism, causing increased ketogenesis and diminished triglyceride synthesis, possibly through potentiation of beta-adrenergic or related pathways. If these concepts prove to be valid in humans, they suggest that factors such as the rate of very-low-density lipoprotein (VLDL) production or the state of sympathetic nervous activity may influence the changes in lipids induced by these agents.