In vitro studies showed that the impaired dilatation in response to acetylcholine in cerebral arteries of rats on a high-salt diet was due to attenuated NO release, while vascular response to bradykinin and to NO donor, and levels of reactive oxygen species were unaltered by elevated dietary salt intake. Although even a short-term high salt diet decreased the ability of blood vessels to relax, low dose angiotensin II infusion restored normal vascular function following short-term intake of high salt diet. Hence, salt-induced angiotensin II suppression caused a profound impairment of vascular relaxation. Taken together, increased infarct volume observed in the present study could occur with excess salt if this high salt leads to impaired vascular relaxation of collateral arterioles or leptomeningeal anastomoses after distal MCAO. The earliest phase of ischemic injury characterized by cytotoxic edema – closely coupled with ionic edema – is followed by the second phase of the breakdown of the BBB with leakage of plasma proteins such as albumin into brain extracellular space. Salt loading increased superoxide production in the brain of SHRSP, and angiotensin II infusion in salt-loaded SHRSP significantly impaired BBB, which was prevented by an angiotensin II type 1 receptor blocker candesartan but not by a calcium channel blocker amlodipine, and this effect was independent of blood pressure level. In contrast to spontaneous stroke, a decrease in apparent diffusion coefficient of water was detected after 2 h of MCAO, but the effects of excess salt on ADC after MCAO were not examined in the study by Guerrini et al.. Subsequent to cytotoxic and ionic edema characterized by increased sodium contents in ischemic tissue, vasogenic edema occurs as also shown in the present study. In the present study, however, excess salt did not affect the extent of brain albumin levels in ischemic brain regions in the salt-loaded group compared with the control group. In acute cerebral ischemia, up-regulated matrix metalloproteinases, especially gelatinases, are closely associated with BBB disruption, edema formation, and hemorrhagic transformation. Yamashita et al. demonstrated that tPA administered just before the reperfusion of 4.5 h suture MCAO, induced dissociation of neurovascular unit, which was prevented by a free radical scavenger, edaravone. Henning et al. demonstrated an unexpectedly high incidence of parenchymal hematomas at later time points, using gradient-echo magnetic resonance imaging.