Inhibition of Brain Swelling after Ischemia-Reperfusion by β-Adrenergic Antagonists: Correlation with Increased K(+) and Decreased Ca(2+) Concentrations in Extracellular Fluid

Infarct size and brain edema following ischemia/reperfusion are reduced by inhibitors of the Na(+), K(+), 2Cl(−), and water cotransporter NKCC1 and by β (1)-adrenoceptor antagonists. NKCC1 is a secondary active transporter, mainly localized in astrocytes, driven by transmembrane Na(+)/K(+) gradients generated by the Na(+),K(+)-ATPase. The astrocytic Na(+),K(+)-ATPase is stimulated by small increases in extracellular K(+) concentration and by the β-adrenergic agonist isoproterenol. Larger K(+) increases, as occurring during ischemia, also stimulate NKCC1, creating cell swelling. This study showed no edema after 3 hr medial cerebral artery occlusion but pronounced edema after 8 hr reperfusion. The edema was abolished by inhibitors of specifically β (1)-adrenergic pathways, indicating failure of K(+)-mediated, but not β (1)-adrenoceptor-mediated, stimulation of Na(+),K(+)-ATPase/NKCC1 transport during reoxygenation. Ninety percent reduction of extracellular Ca(2+) concentration occurs in ischemia. Ca(2+) omission abolished K(+) uptake in normoxic cultures of astrocytes after addition of 5 mM KCl. A large decrease in ouabain potency on K(+) uptake in cultured astrocytes was also demonstrated in Ca(2+)-depleted media, and endogenous ouabains are needed for astrocytic K(+) uptake. Thus, among the ionic changes induced by ischemia, the decrease in extracellular Ca(2+) causes failure of the high-K(+)-stimulated Na(+),K(+)-ATPase/NKCC1 ion/water uptake, making β (1)-adrenergic activation the only stimulus and its inhibition effective against edema.