We examined whether amiloride, an agent that possesses epithelial sodium channel (ENaC) and sodium/hydrogen exchange (NHE) inhibitory activities, would exhibit renal vascular protection in saline-drinking stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP received amiloride (1.0 mg/kg/day, n =6) or deionized water (3 ml/kg/day, n =6) for 5 weeks starting at 61 days of age. Systolic blood pressure (SBP) did not differ between the groups and there was no difference in the average daily urine output, sodium excretion or potassium excretion. Terminal urinary protein excretion, blood urea nitrogen and renal thrombotic microangiopathic lesions were markedly reduced in the amiloride group with no difference in plasma renin activity (PRA). In a survival protocol, SHRSP infused subcutaneously with benzamil (0.7 mg/kg/day, n = 8), a selective ENaC inhibitor, dimethylamiloride (0.7 mg/kg/day, n = 8), a selective NHE inhibitor, or vehicle (n = 7) had comparable SBP. Dimethylamiloride nonetheless prolonged survival of SHRSP (P < 0.005 vs. vehicle) and benzamil-treated SHRSP lived even longer (P < 0.0001 vs. vehicle, P < 0.05 vs. dimethylamiloride). In a separate series, plasma [K+] was elevated by dimethylamiloride (3.4 ± 0.1 mEq/L, n = 8) and benzamil (3.3 ± 0.1 mEq/L, n = 8) relative to vehicle (3.0 ± 0.1 mEq/L, n = 8) at 4 but not 24 h after dosing. These findings suggest the involvement of a sodium transport mechanism in the development of thrombotic microangiopathy in SHRSP, unrelated to marked changes in arterial pressure, PRA, plasma potassium or urinary water and electrolyte excretion.