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Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock

Nature volume 390, pages 518–521 (1997)Cite this article

Abstract

Anandamide, an endogenous cannabinoid ligand1, binds to CB1 cannabinoid receptors2 in the brain and mimics the neurobehavioural actions of marijuana3,4. Cannabinoids and anandamide also elicit hypotension mediated by peripheral CB1 receptors5,6,7,8. Here we report that a selective CB1 receptor antagonist, SR141716A9, elicits an increase in blood pressure in rats subjected to haemorrhagic shock, whereas similar treatment of normotensive rats or intracerebroventricular administration of the antagonist during shock do not affect blood pressure. Blood from haemorrhaged rats causes hypotension in normal rats, which can be prevented by SR141716A but not by inhibition of nitric oxide synthase in the recipient. Macrophages and platelets from haemorrhaged rats elicit CB1 receptor-mediated hypotension in normotensive recipients, and incorporate arachidonic acid or ethanolamine into a product that co-elutes with anandamide on reverse-phase high-performance liquid chromatography. Also, macrophages from control rats stimulated with ionomycin or bacterial phospholipase D produce anandamide, as identified by gas chromatography and mass spectrometry. These findings indicate that activation of peripheral CB1 cannabinoid receptors contributes to haemorrhagic hypotension, and anandamide produced by macrophages may be a mediator of this effect.

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Figure 1: The effects of SR141716A (3 mg kg−1i.v. in 0.2 ml, ▴, n = 7) or vehicle (0.2 ml, ▵, n = 7) on blood pressure in rats subjected to haemorrhagic shock.
Figure 2: SR141716A inhibits the hypotensive response of control rats to i.v. administered mononuclear cells isolated from the blood of haemorrhaged rats.
Figure 3: SR141716A inhibits the hypotensive response of control rats to i.v. injection of mononuclear cells from platelet-depleted blood (a) or of platelet-richplasma (b) obtained from animals in shock.
Figure 4: HPLC analysis of 3H-arachidonic acid metabolites generated in vitro by macrophages isolated from rat blood.
Figure 5: HPLC analysis of 3H-ethanolamine metabolites generated in vitro by macrophages isolated from 3 ml blood from a.
Figure 6: Identification by GC/MS of anandamide generated by macrophages and platelets.

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Acknowledgements

We thank K. Willoughby for help with the HPLC assays, T. Bridgen for help with GC/MS, E. Ishac for preparing illustrations and J. Lowe for providing SR141716A. This work was funded by grants from the American Heart Association Virginia Affiliate and from the National Institutes of Health. J.A.W. was supported by a fellowship from the Deutsche Forschungsgemeinschaft.

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  1. Jens A. Wagner, Kàroly Varga, Earl F. Ellis, Beverly A. Rzigalinski, Billy R. Martin and George Kunos: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, PO Box 980613, Richmond, 23298, Virginia, USA

    Earl F. Ellis, Beverly A. Rzigalinski, Billy R. Martin & George Kunos

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  1. Jens A. Wagner
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  2. Kàroly Varga
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  6. George Kunos
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Correspondence to George Kunos.

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Wagner, J., Varga, K., Ellis, E. et al. Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Nature 390, 518–521 (1997). https://doi.org/10.1038/37371

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