Vol. 304, Issue 1, 179-184, January 2003

Potentiation of Anandamide Effects in Mesenteric Beds Isolated from Endotoxemic Rats

María Luz Orliac, Roxana Peroni, Stella M Celuch and Edda Adler-Graschinsky

Instituto de Investigaciones Farmacológicas-Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina

The aim of the present experiments was to study the effects of exogenously added anandamide on transient norepinephrine (NE)-induced contractions in mesenteric beds isolated from adult male Sprague-Dawley rats 6 h after the i.p. administration of 5 mg kg¹ lipopolysaccharide (LPS). LPS treatment induced a 3-fold increase in total nitric-oxide synthase (NOS) activity without modifying either the systolic blood pressure or the vascular reactivity to NE of the isolated mesenteric bed. The endocannabinoid anandamide (0.01-10 µM) caused concentration-dependent reductions of the contractile responses to NE in the isolated mesenteric bed. This effect was significantly potentiated after LPS treatment compared with the controls. Anandamide-induced reductions of the contractile responses to NE in mesenteric beds isolated from LPS-treated rats were unmodified by endothelium removal but significantly diminished by either the anandamide amidase inhibitor phenylmethylsulfonyl fluoride (200 µM) or the vanilloid receptor antagonist capsazepine (1 µM). The vanilloid receptor agonist capsaicin (0.01-100 nM) also caused concentration-dependent relaxations that were potentiated in mesenteric beds from LPS-treated rats. Nevertheless, they were unmodified by 1 µM capsazepine. It is concluded that the potentiation of anandamide relaxations after LPS treatment, which are evident at early stages of endotoxic shock, could involve the participation of an anandamide metabolite and might be mediated, at least in part, through a vanilloid receptor.