Blood--brain barrier sodium/potassium pump: modulation by central noradrenergic innervation.

Abstract

The active transport of Na+ and K+ across the blood-brain barrier by the membrane-bound enzyme Na+/K+-activated ATPase of brain microvessel endothelial cells has a major role in the maintenance of brain water and electrolyte homeostasis. To test whether the putative noradrenergic innervation of cerebral microvessels from the nucleus locus ceruleus contributes to the regulation of Na+/K+-ATPase activity of the blood-brain barrier, specific [3H]ouabainbinding studies were performed on cerebral microvessels and crude cortical membranes obtained from Wistar rats with unilateral 6-hydroxydopamine lesion of the nucleus locus ceruleus. Such lesion depleted norepinephrine by about 90% in the ipsilateral cerebral cortex without affecting the contralateral cortex.[3lH]Ouabain binding to membranes of cerebral cortex and the cerebral microvessels was specific and saturable. The maximal ouabain-binding capacity in microvessels of the ipsilateral, norepinephrine-depleted, cerebral cortex was reduced by about 40%, without change in the affinity of binding.[3H]Ouabain binding to crude membrane fractions of the cerebral cortex was not significantly affected by locus ceruleus lesion. The results suggest that Na+/K+-ATPase activity of cerebral microvessels, and the consequent transport of Na+ and K+ across the blood-brain barrier, is modulated by noradrenergic innervation from the locus ceruleus.

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

“…Increased levels of 2 and 2 adrenoceptors have been reported in AD [237], suggesting possible alterations of the extrinsic regulation of the microvascular tone, which might contribute to impairing regional CBF distribution. Because microvascular noradrenergic innervation in cerebral microvessels also participates in the regulation of the (Na + /K + )-pump [238] (an important feature of the BBB function which regulates water and electrolyte homeostasis) it could be hypothesised that alteration of noradrenergic innervation could also alter fluid exchange at the BBB, thus creating another potential pathway of impaired CBF distribution. However, quantitative evidence is needed to confront this hypothesis.…”

“…Alterations of the adrenergic microvascular innervation might alter the (Na + /K + )-pump function of the BBB, possibly resulting in fluid balance impairment [238] and dysregulation of regional CBF.…”

Mechanisms of Brain Ion Homeostasis during Acute and Chronic Variations of Plasma Potassium

“…Anatomic data suggest that brain capillaries may be under neuronal con trol, because they receive noradrenergic afferents from the locus ceruleus (Raichle et aI., 1975). Fur thermore, a 40% reduction of Na + ,K + -ATPase content has been described by Harik (1986) in cap illaries isolated from the cerebral cortex of rats 2 weeks after ipsilateral locus ceruleus lesions. Other data suggest that BBB N a + transport may also be modulated hormonally (e.g., Nakao et aI., 1990).…”

Genetic deletion of the norepinephrine transporter decreases vulnerability to seizures

“…However, if this was the case, increased instead of decreased sensitivity to seizures would have been observed. NE has been suggested to modify permeability of the blood brain barrier [10], which may have also altered the penetration of convulsants to the brain. Regardless of whether hemodynamic factors altered brain concentrations of the convulsants, NET deletion was sufficient to reduce seizure vulnerability of the mutants.…”