Elucidation of the temporal relationship between endothelial-derived NO and EDHF in mesenteric vessels

Louise S. Harrington, Martin J. Carrier, Nicola Gallagher, Derek Gilroy, Chris J. Garland, Jane A. Mitchell

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Abstract

Although the endothelium co-generates both nitric oxide ( NO) and endothelium-derived hyperpolarizing factor ( EDHF), the relative contribution from each vasodilator is not clear. In studies where the endothelium is stimulated acutely, EDHF responses predominate in small arteries. However, the temporal relationship between endothelial-derived NO and EDHF over more prolonged periods is unclear but of major physiological importance. Here we have used a classical pharmacological approach to show that EDHF is released transiently compared with NO. Acetylcholine (3 x 10(-6) mol/l) dilated second- and/or third-order mesenteric arteries for prolonged periods of up to 1 h, an effect that was reversed fully and immediately by the subsequent addition of L-NAME (10(-3) mol/l) but not TRAM- 34 (10(-6) mol/l) plus apamin (5 x 10(-7) mol/l). When vessels were pretreated with L-NAME, acetylcholine induced relatively transient dilator responses (declining over similar to 5 min), and vessels were sensitive to TRAM- 34 plus apamin. When measured in parallel, the dilator effects of acetylcholine outlasted the smooth muscle hyperpolarization. However, in the presence of L-NAME, vasodilatation and hyperpolarization followed an identical time course. In vessels from NOSIII-/- mice, acetylcholine induced small but detectable dilator responses that were transient in duration and blocked by TRAM- 34 plus apamin. EDHF responses in these mouse arteries were inhibited by an intracellular calcium blocker, TMB-8, and the phospholipase A(2) inhibitor AACOCF(3), suggesting a role for lipid metabolites. These data show for the first time that EDHF is released transiently, whereas endothelial-derived NO is released in a sustained manner.
Original languageEnglish
Pages (from-to)H1682-H1688
JournalAmerican Journal of Physiology-Heart and Circulatory Physiology
Volume293
Issue number3
DOIs
Publication statusPublished - 2007

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Endothelium
Nitric Oxide
Apamin
Acetylcholine
NG-Nitroarginine Methyl Ester
Arteries
Mesenteric Arteries
Phospholipases A
Vasodilator Agents
Vasodilation
Smooth Muscle
Pharmacology
Calcium
Lipids
TRAM 34

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Elucidation of the temporal relationship between endothelial-derived NO and EDHF in mesenteric vessels. / Harrington, Louise S.; Carrier, Martin J.; Gallagher, Nicola; Gilroy, Derek; Garland, Chris J.; Mitchell, Jane A.

In: American Journal of Physiology-Heart and Circulatory Physiology, Vol. 293, No. 3, 2007, p. H1682-H1688.

Research output: Contribution to journalArticle

Harrington, Louise S. ; Carrier, Martin J. ; Gallagher, Nicola ; Gilroy, Derek ; Garland, Chris J. ; Mitchell, Jane A. / Elucidation of the temporal relationship between endothelial-derived NO and EDHF in mesenteric vessels. In: American Journal of Physiology-Heart and Circulatory Physiology. 2007 ; Vol. 293, No. 3. pp. H1682-H1688.
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AU - Garland, Chris J.

AU - Mitchell, Jane A.

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