Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 153, Issue 1, Pages 132-139Publisher
WILEY
DOI: 10.1038/sj.bjp.0707562
Keywords
middle cerebral artery; posterior cerebral artery; endothelium-dependent relaxation; nitric oxide; endothelium-derived hyperpolarizing factor; nitroglycerine; nitrate tolerance; rabbit
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Background and purpose: In the setting of nitrate tolerance, endothelium-dependent relaxation is reduced in several types of peripheral vessels. However, it is unknown whether chronic in vivo administration of nitroglycerine modulates such relaxation in cerebral arteries. Experimental approach: Isometric force and smooth muscle cell membrane potential were measured in endothelium-intact strips from rabbit middle cerebral artery (MCA) and posterior cerebral artery (PCA). Key results: ACh (0.1-10 mu M) concentration-dependently induced endothelium-dependent relaxation during the contraction induced by histamine in both MCA and PCA. Chronic ( 10 days) in vivo administration of nitroglycerine reduced the ACh-induced relaxation in PCA but not in MCA, in the presence of the cyclooxygenase inhibitor diclofenac ( 3 mu M). In the presence of the NO-synthase inhibitor N-omega-nitro-L-arginine(L-NNA, 0.1 mM) plus diclofenac, in MCA from both nitroglycerine-untreated control and-treated rabbits, ACh (0.1-10 mu M) induced a smooth muscle cell hyperpolarization and relaxation, and these were blocked by the small-conductance Ca2+-activated K+-channel inhibitor apamin ( 0.1 mu M), but not by the large- and intermediate-conductance Ca2+-activated K+-channel inhibitor charybdotoxin ( 0.1 mu M). In contrast, in PCA, ACh (< 3 mu M) induced neither hyperpolarization nor relaxation under these conditions, suggesting that the endothelium-derived relaxing factor is NO in PCA, whereas endothelium-derived hyperpolarizing factor ( EDHF) plays a significant role in MCA. Conclusions and implications: It is suggested that in rabbit cerebral arteries, the function of the endothelium-derived relaxing factor NO and that of EDHF may be modulated differently by chronic in vivo administration of nitroglycerine.
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