The antidiabetic drug metformin lowers blood pressure (BP) more in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY), and the hypotensive effect is enhanced by high dietary salt. To determine whether enhanced hypotension is secondary to greater decreases in sympathetic nerve activity (SNA), we placed WKY and SHR on normal salt (0.3%), and SHR on high salt (8.0%) for 2 weeks and then measured anesthetized BP and lumbar SNA to metformin (0, 10, 50, and 100 mg/kg, given intravenously). Baseline BP were similar in SHR groups but lower in WKY. Although metformin decreased BP more in high salt SHR (50 mg/kg: deltaBP: -23+/-1 mm Hg) than in normal salt SHR (-14+/-1 mm Hg, P< .01) and less in WKY (-10+/-1 mm Hg, P<.05), equivalent decreases in SNA were observed. We conclude that both strain and high salt potentiate acute depressor responses to metformin through mechanisms that are independent of SNA.