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 nM) and histamine (300 nM), we investigated the combined actions of N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin on acetylcholine-induced depressor responses. 2. Under control conditions, acetylcholine (10 nM-30 microM) 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 microM) and indomethacin (10 microM), 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 (G0), a smaller dilatory action on first generation branch arteries (G1) and no effect on second generation branch arteries (G2). In the presence of L-NAME and indomethacin, vasodilatation occurred in G2 with no effect in G0 or G1. 4. Two calcium-activated K+ channels blockers, charybdotoxin (ChTX; 10 nM) and penitrem A (100 nM), further inhibited, but did not abolish, the L-NAME- and indomethacin-resistant response to acetylcholine (10 nM-300 microM). Both agents abolished the vasodilatory action of acetylcholine in G2. 5. In conclusion, L-NAME and indomethacin induced a shift in acetylcholine-induced vasodilatation from G0 and G1 to G2. 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.
Department of Diagnostic Radiology, Cardiovascular Sciences Research Group, University of Wales College of Medicine, Cardiff.
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Berman
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Griffith
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D018999:Charybdotoxin / Q000494:pharmacology; D003864:Depression, Chemical; D004423:Ear / Q000098:blood supply*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009183:Mycotoxins / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D009183:Mycotoxins; D018999:Charybdotoxin; D012701:Serotonin; C003626:tremortin; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin