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Flow‐induced enhancement of vasoconstriction and blockade of endothelium‐derived hyperpolarizing factor (EDHF) by ascorbate in the rat mesentery
Author(s) -
Stirrat A,
Nelli S,
Dowell F J,
Martin W
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707499
Subject(s) - apamin , charybdotoxin , vasodilation , endothelium derived hyperpolarizing factor , mesenteric arteries , myograph , vasoconstriction , chemistry , acetylcholine , endocrinology , medicine , endothelium , pharmacology , nitric oxide , potassium channel , artery
Background and purpose: We previously reported that ascorbate inhibits flow‐ and agonist‐induced, EDHF‐mediated vasodilatation in the bovine ciliary circulation. This study examined whether ascorbate had similar actions in the rat mesenteric vasculature. Experimental approach: The effects of ascorbate were examined both in rat second order mesenteric arterial rings suspended in a static wire myograph and the rat mesentery perfused at different rates of flow. Key results: Ascorbate (50 μM) had no effect on U46619‐induced tone or acetylcholine‐induced, EDHF‐mediated vasodilatation in either rings of mesenteric artery or the perfused mesentery at rates of flow below 10 ml min −1 . At higher rates of flow, ascorbate produced two distinct effects in the rat mesentery: a rapid and maintained enhancement of vasoconstrictor tone and a slow (max at 3 h) inhibition of acetylcholine‐induced, EDHF‐mediated vasodilatation. The enhancement of vasoconstrictor tone appeared to be due to inhibition of flow‐induced EDHF‐like activity, since it was endothelium‐dependent, but could be elicited during blockade of nitric oxide synthase and cyclooxygenase. Despite this, the classical inhibitors of EDHF, apamin and charybdotoxin, failed to affect the ascorbate‐induced enhancement of tone, although they inhibited acetylcholine‐induced vasodilatation. Conclusions and implications: Ascorbate inhibits both flow‐ and agonist‐induced EDHF in the rat mesentery. The strikingly different timecourses of these two effects, together with their differential sensitivity to apamin and charybdotoxin, suggest that the flow‐ and agonist‐induced EDHFs in the rat mesenteric vasculature may either be different entities or operate by different mechanisms. British Journal of Pharmacology (2008) 153 , 1162–1168; doi: 10.1038/sj.bjp.0707499 ; published online 8 October 2007