ACTIVATION OF PERIPHERAL CB1 CANNABINOID RECEPTORS IN HEMORRHAGIC-SHOCK

Anandamide, an endogenous cannabinoid ligand(1), binds to CB1 cannabin oid receptors(2) in the brain and mimics the neurobehavioural actions of marijuana(3,4). Cannabinoids and anandamide also elicit hypotension mediated by peripheral CB1 receptors(5-8). Here we report that a sele ctive CB1 receptor antagonist, SR141716A(9), elicits an increase in bl ood pressure in rats subjected to haemorrhagic shock, whereas similar treatment of normotensive rats or intracerebroventricular administrati on 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 el icit CB1 receptor-mediated hypotension in normotensive recipients, and incorporate arachidonic acid or ethanolamine into a product that co-e lutes with anandamide on reverse-phase high-performance liquid chromat ography. 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 ac tivation of peripheral CB1 cannabinoid receptors contributes to haemor rhagic hypotension, and anandamide produced by macrophages may be a me diator of this effect.