Inhibition of Brain Swelling after Ischemia-Reperfusion by β-Adrenergic Antagonists: Correlation with Increased K+ and Decreased Ca2+ Concentrations in Extracellular Fluid

Abstract EN

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 Ca2+ concentration occurs in ischemia.

Ca2+ 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 Ca2+-depleted media, and endogenous ouabains are needed for astrocytic K+ uptake.

Thus, among the ionic changes induced by ischemia, the decrease in extracellular Ca2+ 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.