The renin-angiotensin-aldosterone system and cardiac natriuretic peptides (atrial and B-type natriuretic peptide, ANP / BNP) are opposing control mechanisms for arterial blood pressure. Accordingly, an inverse relationship between the plasma concentrations of renin (PRC) and ANP exists in most circumstances. However, PRC and ANP levels are both elevated in renovascular hypertension. Because ANP can directly suppress renin release, we used ANP knockout mice (ANP^-/-) to investigate whether high ANP levels attenuate the increase in PRC in response to renal hypoperfusion, thus buffering renovascular hypertension. ANP^-/- mice were hypertensive and had reduced PRC compared with that in ANP^+/+ under control conditions. Unilateral renal artery stenosis (2-kidney, 1-clip, 2k1c) for 1 week induced similar increases in the blood pressure and in the PRC in both genotypes. Unexpectedly, the plasma BNP concentrations in ANP^-/- significantly increased in response to 2k1c, potentially compensating for the lack of ANP. In fact, in mice lacking guanylyl cyclase A (GC-A^-/-), which is the common receptor for both ANP and BNP, the renovascular hypertension was markedly augmented compared with that in GC-A^+/+. However, the higher blood pressure of GC-A^-/- was not caused by a disinhibition of the renin system because the PRC and renal renin synthesis were significantly lower in GC-A^-/- than in GC-A^+/+. Thus, natriuretic peptides buffer renal vascular hypertension via renin-independent effects, such as vasorelaxation. The latter possibility is supported by experiments in isolated perfused mouse kidneys, in which physiological concentrations of ANP and BNP elicited renal vasodilatation and attenuated renal vasoconstriction in response to angiotensin II.