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

1 In the present study, the vasodilator actions of methanandamide and capsa icin in the rat isolated mesenteric arterial bed and small mesenteric arter ial segments were investigated. 2 Methanandamide elicited concentration-dependent relaxations of preconstri cted mesenteric arterial beds (pEC(50) = 6.0+/-0.1, E-max=87+/-3%) and arte rial segments (pEC(50)=6.4+/-0.1, E-max= 93+/-3%). 3 In arterial beds, in vitro capsaicin pre-treatment blocked vasorelaxation to 1 and 3 mu M methanandamide, and reduced to 12+/-7% vasorelaxation to 1 0 mu M methanandamide. Methanandamide failed to relax arterial segments pre -treated in vitro with capsaicin. 4 In arterial beds from rats treated as neonates with capsaicin to cause de struction of primary afferent nerves, methanandamide at 1 and 3 mu M did no t evoke vasorelaxation, and relaxation at 10 mu M methanandamide was reduce d to 26+/-4%. 5 Ruthenium red (0.1 mu M), an inhibitor of vanilloid responses, attenuated vasorelaxation to methanandamide in arterial beds (pEC(50)=5.6+/-0.1, E-ma x=89+/-1%). Ruthenium red at 1 mu M abolished the response to 1 mu M methan andamide, and greatly attenuated relaxation at 3 and 10 mu M methanandamide in arterial beds. In arterial segments, ruthenium red (0.15 mu M) blocked vasorelaxation to methanandamide, but not to CGRP. 6 In arterial segments, the vanilloid receptor antagonist capsazepine (1 mu M) inhibited, and the calcitonin gene-related peptide (CGRP) receptor anta gonist CGRP(8-37) (3 mu M) abolished, methanandamide-induced relaxations. C GRP(8-37), but not capsazepine, attenuated significantly relaxation to exog enous CGRP. 7 These data show that capsaicin and ruthenium red attenuate vasorelaxation to methanandamide in the rat isolated mesenteric arterial bed and small me senteric arterial segments. In addition, CGRP(8-37) and capsazepine antagon ize responses to methanandamide in mesenteric arterial segments. In conclus ion, vanilloid receptors on capsaicin-sensitive sensory nerves play an impo rtant role in the vasorelaxant action of methanandamide in the rat isolated mesenteric arterial bed and small mesenteric arterial segments.