Regulation of blood-brain barrier endothelial cells by nitric oxide.

Abstract

Nitric oxide (NO) synthesized by vascular endothelial cells is a potent vasodilator substance. The actions of NO extend well beyond its vasodilatory properties, and increasingly, NO has been recognized as an important signal for intercellular and intracellular communication. Recently, NO has been implicated in the regulation of vascular and bloodbrain barrier permeability. NO has also been shown to modulate ion channels in excitable cells, thus affecting neuronal firing. We report the results of patch-clamp experiments that show a modulatory action of NO as well as cGMP and cAMP on a hyperpolarization-activated current (Iha) carried by both Na+ and K' ions in blood-brain barrier endothelial cells. lha was recorded in cells dialyzed with 0.2 mmol/L GTP-y-S to inhibit a large inwardly rectifying potassium current. This ionic current and its modulation by NO may play a role in the regulation of the transport of ions, nutrients, and other molecules to the brain and serve as an integral part of the blood-brain barrier. The modulation of Iha by a cyclic guanosine nucleotide may also explain previous reports suggesting a role for NO in the regulation of blood-brain barrier function. (Circ Res. 1994;75:528-538.) Key Words * ion homeostasis * membrane permeability * cyclic nucleotides * hyperpolarization A recisely regulated extracellular ionic environ-A ment in the mammalian central nervous system is vital for normal neuronal function. Capillary and arteriolar endothelial cells (ECs) control the movements of ions and water between blood and brain interstitial fluids; in particular, they regulate the movement of Na+ and K' across the blood-brain barrier,1'2 preventing excessive potassium accumulation in the cerebrospinal fluid (CSF) and maintaining Na+ concentrations sufficiently high for action potential generation. A Na4,K4-ATPase localized on the abluminal side of brain capillaries3,4 and an amiloride-sensitive cation channel,5 acting synergistically with the Na4-Cl-transporter,6 provide a direct path for transendothelial Na+ transport. Potassium transport is primarily directed from the CSF to the blood so that the blood-brain barrier must play a critical role in brain potassium homeostasis.1'4 7Despite the importance of blood-brain barrier function, little is known of the regulation of these ionic fluxes or their modulation by hormones or transmitters.Endothelium-derived relaxing factor (EDRF) has been identified as nitric oxide (NO) synthesized from the guanidino group of L-arginine.89 The continuous release of NO by the endothelium and the resulting activation of the guanylate cyclase signaling cascade have been shown to impact on the permeability of ECs to solutes and larger molecules.10-3 In addition, cGMP caused a decrease in the electrical resistance of in vitro blood-brain barrier endothelial monolayers."4The main voltage-dependent ionic current expressed in ECs belongs to the family of inwardly rectifying Received January 4, 1994; accepted May 20, 1994 potassium currents15-7; thus, ECs are consider...

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