Arterial pressure is age and sex dependent. The angiotensin type 2 receptor (AT 2 R) plays a greater role in the regulation of arterial pressure and renal function in adult females than age-matched males and aging females. In the present study, we investigated the effect of chronic AT 2 R stimulation using the AT 2 R agonist, compound 21 (C21), to attenuate the hypertensive effects of AngII. Mean arterial pressure (MAP) was measured via radiotelemetry in 14 week old male and female mice treated with vehicle, AngII (36 μg/kg/hr), C21 (18 μg/kg/hr), AngII+C21 or AngII+C21 plus PD123319 (AT 2 R antagonist; 125 μg/kg/hr) for 21 days. At the end of the treatment, renal excretory function, angiotensin receptor expression and sodium transporter profiles were assessed. In agreement with previous studies, the pressor response to AngII was greater in male than female mice (35±3 vs 20±4 mmHg respectively, P<0.05). There was no effect of C21 treatment alone on MAP nor did C21 alter the pressor response to AngII in females. However, in males, C21 blunted the pressor response to AngII such that MAP was similar between AngII+C21 males, AngII females and AngII+C21 females (18±2, 20±4 and 17±4 mmHg on day 21, respectively). Co-infusion of PD123319 restored the normal pressor response to AngII in males. Conversely, in females, treatment with AngII+PD123319 or AngII+C21+PD123319 enhanced the pressor response to AngII by ~20 mmHg, to a level seen in AngII males. The renal AT 2 R/AT 1 R ratio was greater in female than male mice and was not affected by treatment. Vehicle treated females had lower proximal versus distal Na+ transporter abundance than males. AngII-treatment increased NCC in both sexes, while proximal and loop transporters (NHE, NHE3-P, NaPi2 and NKCC2) decreased in males only. Treatment with C21 alone did not significantly affect sodium transporters. In males, AngII+C21treatment increased distal transporters and this effect was reversed by PD123319. Conversely, in females, C21 blunted the AngII effect on sodium transporters (claudin-2, NKCC-P, NCC-P and ENaC). Our novel data demonstrate that chronic AT 2 R stimulation attenuates AngII-induced hypertension in adult males, but not females. Thus, AT 2 R agonists may be a novel antihypertensive therapy for males and ageing females.