6-Iodoamiloride, an analogue of the sodium channel blocker amiloride, is a vasodilator-depressor, diuretic-natriuretic, and antikaliuretic agent. In these experiments we intravenously infused 6-iodamiloride (0.38 mg/100 g body weight) over a 10- to 11-minute period into rats with reduced renal mass-saline hypertension or one-kidney, one clip hypertension. The infusion produced a prompt but transient fall in blood pressure. These findings are in contrast to those in spontaneously hypertensive rats (SHR), in which the same infusion of 6-iodoamiloride produced a prompt, pronounced, and sustained fall in blood pressure. Studies from a number of laboratories suggest that vascular smooth muscle cells from the SHR have increased permeability to sodium whereas vascular smooth muscle cells from the other two models do not. Thus, 6-iodoamiloride may have potential both as a diagnostic probe and a therapeutic agent for hypertension characterized by increased vascular smooth muscle cell permeability to sodium.