Vanilloid receptors on capsaicin‐sensitive sensory nerves mediate relaxation to methanandamide in the rat isolated mesenteric arterial bed and small mesenteric arteries

In the present study, the vasodilator actions of methanandamide and capsaicin in the rat isolated mesenteric arterial bed and small mesenteric arterial segments were investigated. Methanandamide elicited concentration-dependent relaxations of preconstricted mesenteric arterial beds (pEC50=6.0±0.1, Emax=87±3%) and arterial segments (pEC50=6.4±0.1, Emax=93±3%). In arterial beds, in vitro capsaicin pre-treatment blocked vasorelaxation to 1 and 3 μM methanandamide, and reduced to 12±7% vasorelaxation to 10 μM methanandamide. Methanandamide failed to relax arterial segments pre-treated in vitro with capsaicin. In arterial beds from rats treated as neonates with capsaicin to cause destruction of primary afferent nerves, methanandamide at 1 and 3 μM did not evoke vasorelaxation, and relaxation at 10 μM methanandamide was reduced to 26±4%. Ruthenium red (0.1 μM), an inhibitor of vanilloid responses, attenuated vasorelaxation to methanandamide in arterial beds (pEC50=5.6±0.1, Emax=89±1%). Ruthenium red at 1 μM abolished the response to 1 μM methanandamide, and greatly attenuated relaxation at 3 and 10 μM methanandamide in arterial beds. In arterial segments, ruthenium red (0.15 μM) blocked vasorelaxation to methanandamide, but not to CGRP. In arterial segments, the vanilloid receptor antagonist capsazepine (1 μM) inhibited, and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP8–37 (3 μM) abolished, methanandamide-induced relaxations. CGRP8–37, but not capsazepine, attenuated significantly relaxation to exogenous CGRP. These data show that capsaicin and ruthenium red attenuate vasorelaxation to methanandamide in the rat isolated mesenteric arterial bed and small mesenteric arterial segments. In addition, CGRP8–37 and capsazepine antagonize responses to methanandamide in mesenteric arterial segments. In conclusion, vanilloid receptors on capsaicin-sensitive sensory nerves play an important role in the vasorelaxant action of methanandamide in the rat isolated mesenteric arterial bed and small mesenteric arterial segments. British Journal of Pharmacology (2000) 130, 1483–1488; doi:10.1038/sj.bjp.0703456