Chronic activation of the renin angiotensin system leads to hypertension and ultimately target organ injury. In the kidney, typical early signs are microvascular dysfunction, hypoxia, inflammation and ultimately fibrosis/necrosis. We found previously that the F344 rat is particularly susceptible to renal injury following chronic angiotensin II (ANGII) infusion. We further identified p2rx7, encoding the P2X7 receptor (P2X7R), as a candidate gene for this differential susceptibility (Menzies et al. Front. Physiol. 4:305 2013). Here we have tested the hypothesis that P2X7R antagonism improves vascular function under high ANGII tone. Osmotic minipump containing ANG II (30ng/min) or saline vehicle were implanted into male F344 rats under isofluorane anesthesia. After 14 days, rats were again anaethetised (Thiobutabarbital; 120mg/kg) for measurement of blood pressure and the acute pressure natriuresis response. Chronic ANGII increased blood pressure by (ANGII=133±2; Vehicle=118±2 mmHg; P<0.01). The acute pressure natriuresis response was induced by sequential ligation of the coeliac artery and mesenteric artery. Each step evoked a ~15mmHg increment in blood pressure and an increase in urinary sodium excretion. This natriuresis was significantly blunted in the ANGII-treated group. Renal medullary perfusion, measured by Doppler flux, was also reduced (ANGII=6.50 ± 2.7; Vehicle=12.02 ± 3.5 TPU; P<0.05) and the cortico-medullary oxygenation gradient, as determined by BOLD MRI, disrupted in ANGII-treated animals. Selective P2X7R antagonism restored pressure natriuresis, promoting a significant leftward shift in the intercept and increasing the gradient of the response. Sodium excretion was increased 6 fold and blood pressure normalised. The specific P2X7R antagonist AZ11657312 increased renal medullary perfusion, but only in ANGII-treated rats. Tissue oxygenation was improved by P2X7R blockade, particularly in poorly oxygenated regions of the kidney. These data suggest that tonic P2X7R activation induces renal vascular dysfunction under high ANGII tone. P2X7R antagonism reduces blood pressure, increases perfusion of the renal medulla and imporves regional oxygenation of the kidney. Thus, P2X7R antagonism could provide broad therapeutic value in the early stages of renal disease.