Imaging the transmembrane and transendothelial sodium gradients in gliomas

Under normal conditions, high sodium (Na(+)) in extracellular (Na(+)(e)) and blood (Na(+)(b)) compartments and low Na(+) in intracellular milieu (Na(+)(i)) produce strong transmembrane (ΔNa(+)(mem)) and weak transendothelial (ΔNa(+)(end)) gradients respectively, and these manifest the cell membrane potential (V(m)) as well as blood–brain barrier (BBB) integrity. We developed a sodium ((23)Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic polyanionic agent to measure ΔNa(+)(mem) and ΔNa(+)(end). In vitro (23)Na-MRSI established that the (23)Na signal is intensely shifted by the agent compared to other biological factors (e.g., pH and temperature). In vivo (23)Na-MRSI showed Na(+)(i) remained unshifted and Na(+)(b) was more shifted than Na(+)(e), and these together revealed weakened ΔNa(+)(mem) and enhanced ΔNa(+)(end) in rat gliomas (vs. normal tissue). Compared to normal tissue, RG2 and U87 tumors maintained weakened ΔNa(+)(mem) (i.e., depolarized V(m)) implying an aggressive state for proliferation, whereas RG2 tumors displayed elevated ∆Na(+)(end) suggesting altered BBB integrity. We anticipate that (23)Na-MRSI will allow biomedical explorations of perturbed Na(+) homeostasis in vivo.