Abstract-Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes mellitus, lowers blood pressure in humans and experimental animals. We recently demonstrated that short-term administration of metformin may lower blood pressure by reducing sympathetic neural outflow. The present studies were initiated to determine whether long-term administration of metformin blunts salt-induced hypertension, a condition characterized by elevated sympathetic activity. Male spontaneously hypertensive rats, in which radiotelemeters had been implanted for continuous monitoring of heart rate and blood pressure, were randomly assigned to groups that received vehicle (drinking water) or metformin (500 mg/kg per day) and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not affect blood pressure in the animals that ate the normal-salt diet (vehicle, 130Ϯ3 mm Hg; metformin, 133Ϯ5 mm Hg; meanϮSEM), drug treatment blunted the rise in pressure caused by a high-salt diet (vehicle, 153Ϯ4 mm Hg; metformin, 140Ϯ5 mm Hg; PϽ0.001). In agreement, during direct pressure recordings in anesthetized rats, the animals that ate the high-salt diet had higher pressures (136Ϯ13 mm Hg) than those in the control (98Ϯ5 mm Hg, PϽ0.01), metformin (100Ϯ7 mm Hg, PϽ0.01), and metformin/high-salt groups (92Ϯ3 mm Hg, PϽ0.01). Finally, metformin lowered heart rate in rats that ate the normal-and high-salt diets (310Ϯ3 and 305Ϯ4 bpm) compared with rats that ate normal-and high-salt diets given vehicle (332Ϯ3 and 324Ϯ2 bpm, PϽ0.01). These data indicate that the chronic depressor actions of metformin are enhanced in animals with hypertension exacerbated by a high-salt diet. (Hypertension. 1999;33:1135-1140.)