Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 17, Pages 9747-9752Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.97.17.9747
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In addition to nitric oxide (NO) and prostacyclin (PGl(2)) the endothelium generates the endothelium-derived hyperpolarizing factor (EDHF). We set out to determine whether an EDHF-like response can be detected in wild-type (WT) and endothelial NO synthase knockout mice (eNOS -/-) mice. Vasodilator responses to endothelium-dependent agonists were determined in vivo and in vitro. In vivo, bradykinin induced a pronounced, dose-dependent decrease in mean arterial pressure (MAP) which did not differ between WT and eNOS -/- mice and was unaffected by treatment with N-omega-nitro-L-arginine methyl ester and diclofenac. In the saline-perfuse hindlimb of WT and eNOS -/- mice, marked N-omega-nitro-L-arginine (L-NA, 300 mu mol/liter)- and diclofenac-insensitive vasodilations in response to both bradykinin and acetylcholine (ACh) were observed, which were more pronounced than the agonistinduced vasodilation in the hindlimb of WT in the absence of L-NA. This endothelium-dependent, NO/PGl(2)-independent vasodilatation was sensitive to KCl (40 mM) and to the combination of apamin and charybdotoxin. Cap junction inhibitors (18 alpha-glycyrrhetinic acid, octanol, heptanol) and CB-1 cannabinoid-receptor agonists (Delta 9-tetrahydrocannabinol, HU210) impaired EDHF-mediated vasodilation, whereas inhibition of cytochrome P450 enzymes, soluble guanylyl cyclase, or adenosine receptors had no effect on EDHF-mediated responses. These results demonstrate that in murine resistance vessels the predominant agonist-induced endothelium-dependent vasodilation in vivo and in vitro is not mediated by NO, PGl(2), or a cytochrome P450 metabolite, but by an EDHF-like principle that requires functional gap junctions.
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