ENDOTHELIUM-DEPENDENT SENSORY NANC VASODILATATION - INVOLVEMENT OF ATP, CGRP AND A POSSIBLE NO STORE

1 Non-adrenergic We have investigated the mechanisms of the NANC dilat or response in the isolated small mesenteric artery of the rabbit by u se of the tension myograph. 2 Small second or third order (150-300 mu m in diameter) arteries of the rabbit mesenteric bed were mounted in a Mulvany tension myograph. Responses to electrical field stimulation ( EFS) and exogenous vasodilators were investigated. 3 EFS (0.5-16 Hz, 1 0 V, 0.3 ms for 5 s), in the presence of guanethidine (5 mu M) and atr opine (1 mu M) produced frequency-dependent relaxation of small arteri es. Pretreatment with tetrodotoxin (1 mu M) abolished the relaxation a nd desensitization with capsaicin (10 mu M) strongly inhibited the rel axation. 4 Pretreatment with a P2Y-purinoceptor antagonist, basilen bl ue (3 mu M) or a human calcitonin gene-related peptide (hCGRP) recepto r antagonist, hCGRP(8-37) (1 mu M) suppressed the NANC relaxation by a pproximately 40-60 % in each case and combined pretreatment almost abo lished the relaxation. 5 The EFS-induced relaxation was suppressed by endothelium-removal, pretreatment with the soluble guanylyl cyclase in hibitor ODQ (1 mu M) and the NO scavenger oxyhaemoglobin (OxyHb; 20 mu M) but not by NO synthase inhibitors N-G-nitro-L-arginine methyl este r (L-NAME; 300 mu M) or N-G-nitro-L-arginine (L-NOARG; 300 mu M). Comb ined pretreatment with ODQ and CGRP(8-37) almost abolished the relaxat ion. 6 A P2Y-purinoceptor agonist; 2-methylthio ATP, produced endothel ium-dependent relaxation which was inhibited by L-NAME and ODQ (1 mu M ), whilst hCGRP produced endothelium-independent and ODQ-insensitive r elaxation. 7 Ultraviolet light (320 nm, 5 shots over 20 s) produced re laxation that was blocked by both OxyHb and ODQ but not by N-G-monomet hyl-L arginine (L-NMMA, 300 mu M). 8 The present study suggests that E FS-induced NANC relaxation of the mesenteric small artery of the rabbi t is mediated mainly by capsaicin-sensitive sensory C-fibres and that both ATP and CGRP are involved. The action of ATP released by EFS appe ars to be endothelium-dependent and involve activation of soluble guan ylyl cyclase, but is resistant to inhibitors of NO synthase. The respo nse to CGRP is endothelium-independent. These results show that ATP an d CGRP account fully for the NANC relaxation of this vessel type and t hat the endothelium is involved in NANC-induced relaxation. The endoth elium-dependent part of the response is consistent with the release of NO, either from NO synthase, incompletely inhibited by the NO synthas e inhibitors, or by some preformed stores.