Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice

Zoltán Járai, Jens A. Wagner, Sravan Kumar Goparaju, Lei Wang, Raj K. Razdan, Takayuki Sugiura, Ann M. Zimmer, Tom I. Bonner, Andreas Zimmer, George Kunos

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Abstract

Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid receptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural ligand of CB1 receptors. In the present study, we examined the effects of 2-AG on mean arterial pressure and heart rate in anesthetized mice and assessed the role of CB1 receptors through the use of selective cannabinoid receptor antagonists and CB1 receptor knockout (CB1(-/-)) mice. In control ICR mice, intravenous injections of 2-AG or its isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia that are unaffected by the CB1 receptor antagonist SR141716A. The same dose of SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and attenuates the bradycardic effect of anandamide. 2-AG elicits a similar hypotensive effect, resistant to blockade by either SR141716A or the CB2 antagonist SR144528, in both CB1(-/-) mice and their homozygous (CB1(+/+)) control littermates. In ICR mice, arachidonic acid (AA, 15 nmol/g IV) elicits hypotension and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypotensive effect of both AA and 2-AG. Synthetic 2- AG incubated with mouse blood is rapidly (<2 minutes) and completely degraded with the parallel appearance of AA, whereas anandamide is stable under the same conditions. A metabolically stable ether analogue of 2-AG causes prolonged hypotension and bradycardia in ICR mice, and both effects are completely blocked by SR141716A, whereas the same dose of 2-AG-ether does not influence blood pressure and heart rate in CB1(-/-) mice. These findings are interpreted to indicate that exogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, which masks its ability to interact with CB1 receptors. Although the observed cardiovascular effects of 2-AG probably are produced by an arachidonate metabolite through a noncannabinoid mechanism, the CB1 receptor-mediated cardiovascular effects of a stable analogue of 2-AG leaves open the possibility that endogenous 2-AG may elicit cardiovascular effects through CB1 receptors.

Original languageEnglish
Pages (from-to)679-684
Number of pages6
JournalHypertension
Volume35
Issue number2
DOIs
Publication statusPublished - Feb 2000

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Keywords

  • Cannabinoid
  • Hypotension
  • Mice
  • Receptors

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Járai, Z., Wagner, J. A., Goparaju, S. K., Wang, L., Razdan, R. K., Sugiura, T., Zimmer, A. M., Bonner, T. I., Zimmer, A., & Kunos, G. (2000). Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice. Hypertension, 35(2), 679-684. https://doi.org/10.1161/01.HYP.35.2.679