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Fluid administration is a key component in the management of acute ischemic stroke (AIS). However, the effects of different sodium concentrations in resuscitation fluids, particularly on distal organ function, remain controversial. This study compared the impact of four commonly used fluids-0.9% isotonic saline (ISO), 0.45% hypotonic saline (HYPO), 1.5% hypertonic saline (HYPER), and 5% glucose (GLUCO)-on perilesional brain tissue, lungs, and kidneys following AIS. AIS was induced in 28 male Wistar rats. Three hours after stroke induction, animals were randomized to receive one of the four fluids. In the brain, the ISO group showed significantly higher expression of versican and hyaluronan compared to the HYPER group (p = 0.022 and p = 0.018, respectively). Conversely, the HYPER group exhibited significantly elevated levels of interleukin-1β (IL-1β), vascular cell adhesion molecule-1 (VCAM-1), and zonula occludens-1 (ZO-1) compared to the GLUCO group (p = 0.01, p = 0.02, and p = 0.006, respectively). In the lungs, the ISO group demonstrated less alveolar collapse and pulmonary edema compared to the HYPER and HYPO groups (p = 0.01 and p = 0.007, respectively). In the kidneys, both the ISO and HYPO groups showed significantly less brush-border injury than the HYPER group (p = 0.007 and p = 0.032, respectively). Furthermore, blood chloride levels declined over time in the ISO group compared to the others. In conclusion, isotonic fluid administration resulted in the least amount of injury to the brain, lungs, and kidneys in this experimental model of AIS, supporting its use as a preferred resuscitation strategy in the acute phase.