Mesenteric vasodilation mediated by endothelial anandamide receptors

Jens A. Wagner, Károly Varga, Zoltán Járai, George Kunos

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Abstract

Cannabinoids, including the endogenous ligand anandamide (arachidonyl ethanolamide), elicit pronounced hypotension in rats via activation of peripherally located CB1 cannabinoid receptors, which have been also implicated in endotoxin (lipopolysaccharide [LPS])-induced hypotension. The present study was designed to test the role of vascular CB1 receptors in cannabinoid- and endotoxin-induced mesenteric vasodilation. In the isolated, buffer-perfused rat mesenteric arterial bed precontracted with phenylephrine, anandamide induced long-lasting (up to 60 minutes) dose-dependent vasodilation (ED50: 79±3 nmol; maximal relaxation: 77±2%), inhibited by 0.5 to 5.0 μmol/L of the selective CB1 receptor antagonist SR141716A. Low doses of the calcium ionophore ionomycin also caused mesenteric vasodilation inhibited by SR141716A. The metabolically stable analogue R-methanandamide elicited mesenteric vasodilation (ED50: 286±29 nmol), whereas the potent synthetic CB1 receptor agonists WIN 55212-2 and HU-210 caused no change in vascular tone or only a minor dilator effect not affected by SR141716A, respectively. The endogenous ligand 2-arachidonyl glycerol caused no change in vascular tone, whereas Δ9-tetrahydrocannabinol and arachidonic acid caused mesenteric vasoconstriction. After endothelial denudation, the dilator response to anandamide was slightly reduced and was no longer inhibited by SR 141716A. In preparations from LPS-pretreated rats, SR 141716A alone caused a significant and prolonged increase in perfusion pressure, whereas it had no such effect in control preparations perfused in vitro with or without LPS or after endothelial denudation in preparations from rats pretreated with LPS. We conclude that anandamide-induced mesenteric vasodilation is mediated by an endothelially located SR141716A-sensitive 'anandamide receptor' distinct from CB1 cannabinoid receptors and that activation of such receptors by an endocannabinoid, possibly anandamide, contributes to LPS-induced mesenteric vasodilation in vivo.

Original languageEnglish
Pages (from-to)429-434
Number of pages6
JournalHypertension
Volume33
Issue number1 II
Publication statusPublished - Jan 1 1999

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Keywords

  • Anandamide
  • Cannabinoids
  • Endotoxin
  • Vasodilation

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Wagner, J. A., Varga, K., Járai, Z., & Kunos, G. (1999). Mesenteric vasodilation mediated by endothelial anandamide receptors. Hypertension, 33(1 II), 429-434.