receptors, the dual RAS blockade was shown to be more effective than doubling the usual dose of an AT1R antagonist through more efficient blockade of the RAS. 26 This may offer an alternative strategy for treating patients with various renin levels and may potentially increase the cardioprotective and nephroprotective benefits by more complete RAS blockade. Subsequently, studies in various rat models of hypertension with either normal27, 28 or high renin levels29 confirmed that the BP-lowering effect of the combined RAS blockade enables the individual dosages of each drug in the combination to be 3 to 10 times lower than when used separately to achieve the same BP-lowering effect. However, this BP response to the combined RAS blockade appears to be finite. If the doses of each single-site blocker are increased toward a “maximal” inhibition of the RAS, the synergistic effect of combination therapy is not observed at peak effect, 28 and the magnitude of the decrease in BP remains salt-dependent as it is with a single-site RAS blocker.