- Paper Report
- Open Access
Endothelium-derived hyperpolarizing factor
- Shu Fang Liu1
© Biomed Central Ltd 2001
- Received: 15 September 2000
- Accepted: 19 September 2001
- Published: 19 September 2001
- endothelium-derived hyperpolarizing factor
- nitric oxide
At least three different vasodilating agents are synthesized and released by the endothelium. Although the properties of NO and prostacyclin have been extensively investigated, the nature and mechanism of action of EDHF is still controversial. This paper characterizes EDHF-mediated responses using eNOS knockout mice.
The authors compared the vasodilator responses to endothelium-dependent agonists, Ach, BK and the endothelium-independent vasodilator, sodium nitroprusside, in vitro and in vivousing wild-type and eNOS(-/-) mice.
Baseline mean arterial pressure (MAP) was significantly lower in wild-type than in eNOS(-/-) mice. A combined diclofenac (cyclooxygenase inhibitor) and L-NAME (NOS inhibitor) treatment significantly increased MAP in wild-type, but slightly decreased MAP in eNOS(-/-) mice. In vivo, BK decreased MAP to an identical extent in wild-type and eNOS(-/-) mice, which was not affected by combined L-NAME and diclofenac treatment. Ach induced a concentration-dependent relaxation of isolated artery rings from wild-type, but not eNOS(-/-) mice. The Ach response was completely inhibited by L-NAME plus diclofenac. In the perfused hindlimb preparation pretreated with diclofenac, Ach and BK induced a dose-dependent vasodilator response in both wild-type and eNOS(-/-) mice. This response was well preserved after perfusion with L-NAME (300 μM, 30 min) in both mice. The diclofenac- and L-NAME-resistant vasodilator response was blocked by high K+ concentration, inhibited by K+ channel blockers (a combination of charybdotoxin and apamin) and gap junction inhibitors, attenuated by soluble guanylyl cyclase inhibitor and CB receptor agonists, but was not affected by the adenosine antagonist, the CYP inhibitors, a combination of phospholipase A2 and D inhibitors, catalase and hemeoxygenase inhibitor.
This study demonstrates that endothelial stimulation releases an EDHF that is a potent endogenous vasodilator of murine resistance vessels both in vivo and in vitro, and that EDHF is able to completely compensate for the lack of NO in L-NAME-treated wild-type or eNOS(-/-) / mice. The authors suggest that functional gap junctions and calcium-dependent K+ channels, but not CYP enzymes, soluble guanylyl cyclase, or eNOS play important roles in EDHF-mediated dilation in the mouse hindlimb.
- Brandes RP, Schmitz-Winnenthal F-H, Félétou M, Gödecke A, Huang PL, Vanhoutte P, Fleming I, and Busse R: An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild type and endothelial NO synthase knockout mice. Proc Natl Acad Sci USA. 2000, 97: 9747-9752.View ArticleGoogle Scholar