Increased dietary K⁺ increases plasma [ K⁺] and is linked to or associated with reduced mortality from stroke and reduced blood pressure in humans and animals. We hypothesized that physiologic increases in extracellular [K⁺] ([K]0 ) directly inhibit cultured vascular smooth muscle cell (VSMC) proliferation. Studies were performed by stimulating quiescent cultured canine coronary artery and A₇r₅ VSMC with 5% serum at varying [K]0 starting on day 0. When plated at 5,200 cells/cm² A₇r₅ VSMC counts increased 121% by day 2 and 190% by day 6 in 3 mmol/L [ K ] 0 / but only 21% by day 2 and 45% by day 6 in 7 mmol/L [K]0 ; intermediate [K]0 yielded intermediate proliferative rates. Serum caused a four- to fivefold increase in cell counts of cultured canine coronary artery VSMC in 7 days at 2 mmol/L [ K ] 0 of 2 mmol/L, and increasing [ K ] 0 to 7 mmol/L reduced proliferation by 68%. Uptake of [₃H]thymidine by cultured canine coronary artery VSMC was inhibited by 50% between 2 and 7 mmol/L [K]0 . Increased [K]0 may act by decreasing intracellular Na⁺ ([Nal]_i). Exposure to serum for 24 h more than doubles canine coronary artery [Na]_i, an effect previously associated with VSMC proliferation, and increased [ K ] 0 (from 2 to 7 mmol/L) reduces [Na^ by 74% before and 64% 24 h after serum. We conclude that physiologic increases in [K]0 reduce [Na]_i and proliferation of cultured VSMC. Similar effects occurring in vivo may help to account for the ability of increased dietary K⁺to prevent vascular lesions. Am J Hypertens 1994;7:346-350