Spatial heterogeneity in the mechanisms contributing to acetylcholine‐induced dilatation in the rabbit isolated ear

1 Using an X‐ray microangiographic technique in rabbit isolated perfused ears preconstricted with 5‐HT (300 n m ) and histamine (300 n m ), we investigated the combined actions of N ω ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME) and indomethacin on acetylcholine‐induced depressor responses. 2 Under control conditions, acetylcholine (10 n m –30 μ m ) induced a concentration‐dependent reversal of the pressor response, reaching a maximum of 66.0±13.6% ( n = 6). In the presence of l ‐NAME (300 μ m ) and indomethacin (10 μ m ), this depressor action was reduced, reaching a maximum of 38.6±5.9% ( n = 6). 3 The control response was associated with substantial vasodilatation in the central ear artery (G 0 ), a smaller dilatory action on first generation branch arteries (G 1 ) and no effect on second generation branch arteries (G 2 ). In the presence of l ‐NAME and indomethacin, vasodilatation occurred in G 2 with no effect in G 0 or G 1 . 4 Two calcium‐activated K + channels blockers, charybdotoxin (ChTX; 10 n m ) and penitrem A (100 n m ), further inhibited, but did not abolish, the l ‐NAME‐ and indomethacin‐resistant response to acetylcholine (10 n m –300 μ m ). Both agents abolished the vasodilatory action of acetylcholine in G 2 . 5 In conclusion, l ‐NAME and indomethacin induced a shift in acetylcholine‐induced vasodilatation from G 0 and G 1 to G 2 . This is consistent with the suggestion that nitric oxide dominates in larger vessels whilst other mechanisms dominate in smaller vessels. The l ‐NAME‐ and indomethacin‐resistant component was inhibited by ChTX and penitrem A, suggesting it is mediated, at least in part, by activation of K Ca channels and could therefore involve a hyperpolarising mediator such as endothelium‐derived hyperpolarising factor.British Journal of Pharmacology (1998) 124 , 1245–1253; doi: 10.1038/sj.bjp.0701945