Heterogeneity in the mechanisms of vasorelaxation to anandamide in resistance and conduit rat mesenteric arteries

Authors


School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH. E-mail: saoirse.o'sullivan@nottingham.ac.uk

Abstract

  • In order to address mechanistic differences between arterial vessel types, we have compared the vasorelaxant actions of anandamide in resistance (G3) and conduit (G0) mesenteric arteries.

  • Anandamide produced concentration-dependent relaxations of pre-constricted G3 arteries with a maximal response that was significantly greater than seen in G0.

  • The CB1 receptor selective antagonists SR141716A (100 nM) and AM251 (100 nM) caused reductions in the vasorelaxant responses to anandamide in both arteries. Maximal vasorelaxant responses to anandamide were reduced in both arteries after treatment with capsaicin to deplete sensory neurotransmitters (10 μM for 1 h).

  • Vasorelaxation to anandamide was not affected by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 300 μM) in either artery. Only responses in G3 arteries were sensitive to removal of the endothelium. In G3 vessels only, vasorelaxation to anandamide was reduced by inhibition of EDHF activity with a combination of charybdotoxin (100 nM) and apamin (500 nM) in the presence of L-NAME (300 μM) and indomethacin (10 μM).

  • Antagonism of the novel endothelial cannabinoid receptor (O-1918, 1 μM) caused a reduction in the sensitivity to anandamide in G3 but not G0.

  • G3, but not G0, vessels showed a small reduction in vasorelaxant responses to anandamide after inhibition of gap junctional communication with 18α-GA (100 μM).

  • These results demonstrate that there are differences in the mechanisms of vasorelaxation to anandamide between conduit and resistance mesenteric arteries. In small resistance vessels, vasorelaxation occurs through stimulation of vanilloid receptors, CB1 receptors, and an endothelial receptor coupled to EDHF release. By contrast, in the larger mesenteric artery, vasorelaxation is almost entirely due to stimulation of vanilloid receptors and CB1 receptors, and is endothelium-independent.

British Journal of Pharmacology (2004) 142, 435–442. doi:10.1038/sj.bjp.0705810

Ancillary