Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock

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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.