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(Circulation Research. 2000;87:323.)
© 2000 American Heart Association, Inc.

Cellular Biology

Human Brain Capillary Endothelium

2-Arachidonoglycerol (Endocannabinoid) Interacts With Endothelin-1

Ye Chen, Richard M. McCarron, Yukoh Ohara, Joliet Bembry, Nabil Azzam, Fred A. Lenz, Esther Shohami, Raphael Mechoulam, Maria Spatz

From the Naval Medical Research Center (R.M.M.C., Y.O.), Bethesda, Md; Department of Neurosurgery (F.A.L.), Johns Hopkins University School of Medicine, Baltimore, Md; Hebrew University (E.S., R.M.), Jerusalem, Israel; Stroke Branch (Y.C., J.B., N.A., M.S.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md.

Correspondence to Maria Spatz, MD, National Institutes of Health, NINDS, Stroke Branch, 36 Convent Dr, MSC 4128, Bethesda, MD 20892-4128. E-mail spatzm{at}ninds.nih.gov

Abstract—In brain, the regulatory mechanism of the endothelial reactivity to nitric oxide and endothelin-1 may involve Ca²⁺, cytoskeleton, and vasodilator-stimulated phosphoprotein changes mediated by the cGMP/cGMP kinase system.¹ Endothelium of human brain capillaries or microvessels is used to examine the interplay of endothelin-1 with the putative vasorelaxant 2-arachidonoyl glycerol, an endogenous cannabimimetic derivative of arachidonic acid. This study demonstrates that 2-arachidonoyl glycerol counteracts Ca²⁺ mobilization and cytoskeleton rearrangement induced by endothelin-1. This event is independent of nitric oxide, cyclooxygenase, and lipoxygenase and is mediated in part by cannabimimetic CB1 receptor, G protein, phosphoinositol signal transduction pathway, and Ca²⁺-activated K⁺ channels. The induced rearrangements of cellular cytoskeleton (actin or vimentin) are partly prevented by inhibition of protein kinase C or high levels of potassium chloride. The 2-arachidonoyl glycerol–induced phosphorylation of vasodilator-stimulated phosphoprotein is mediated by cAMP. These findings suggest that 2-arachidonoyl glycerol may contribute to the regulation of cerebral capillary and microvascular function.

Key Words: brain endothelial function • 2-arachidonoglycerol • endothelin-1 • endothelium • cannabinoids

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