We studied the effects of factors that alter active Na extrusion on microvascular smooth muscle contraction. As an index of contraction, we measured arterial pressure in perfused isolated rat hindlimbs. The perfusate was oxygenated Krebs-Henseleit solution containing 0-5.9 mM K+, 4% dextran-40, and, in some instances, dog red cells (6-15% hematocrit). The reference solutions contained 5.9 mM K+. Lowering [K+]oby 50%, or more, substantially increased perfusion pressure reversibly; pressure was inversely related to [K+]o. Treatment with 10"3M ouabain, which should completely inhibit Na-K pumps, caused a greater pressure increase than did nominally K+-free media. These effects were observed in the hindumbs of reserpine-treated (catecholamine-depleted) as well as normal rats and, thus, cannot be explained by modulation of catecholamine release. Perfusion with solutions containing a constant concentration of norepinephrine increased the perfusion pressure with 5.9 HIM K present and augmented the responses to both reduced [K+]oand ouabain. The data are discussed in terms of two mechanisms that may lead to a rise in cell Ca2+: (1) inhibition of electrogenic Na-K pumps may cause the smooth muscle fibers to depolarize slightly, thereby activating a Ca2+conductance increase or release of stored Ca2+, and/or (2) the rise in cell Na*, due to Na-K pump inhibition, may cause the fibers to gain Ca2+by means of Na-Ca exchange.Circ Res 46: 463-470, 1980