The hemodynamic effect of moderate K+depletion in hypertension is unknown. Since severe K+depletion reduces systemic vascular resistance in normotensive rats, we determined the effect of K+depletion on the natural history of hypertension in spontaneously hypertensive rats (SHR). Wistar-Kyoto rats (WKY) and SHR were fed a K+-replete, a moderately K+-depleted, or a severely K+-depleted diet. After 6 weeks, systemic vascular resistance was reduced by 25% in WKY on the severely K+-depleted diet while mean arterial pressure and systemic vascular resistance were comparable in WKY on the other two diets. In SHR on the severely K+-depleted diet for 6 weeks, muscle K+was reduced by 23% and growth rate by 65%. In SHR on the moderately K+-depleted diet, growth rate was reduced by 23% after 3 weeks. By 6 weeks, however, muscle K+was reduced by 5 to 6% and growth rate was comparable to that in SHR receiving the K+-replete diet. The administration of either K+-depleted diet prevented the development of hypertension (systolic blood pressure: severely depleted, 116 ± 4; moderately depleted, 122 ± 3; K+-replete, 155 ± 5 nun Hg;p< 0.001 compared with both K+-depleted groups) and reversed established hypertension (systolic blood pressure: severely depleted, 116 ± 4; moderately depleted, 128 ± 3; K+-replete, 171 ± 5 mm Hg;p< 0.001 compared with both K+-depleted groups). The protective effect of K+depletion was mediated by a 40% reduction in systemic vascular resistance. These results suggest that K+depletion has a potent antihypertensive effect in SHR. The vasodilative effect of moderate K+depletion also appears to be specific for hypertension since it did not occur in normotensive WKY.