Trends in Pharmacological Sciences
ReviewEDHF: bringing the concepts together
Section snippets
Pivotal role of Ca2+ and endothelial Ca2+-activated K+ channels in the EDHF pathway
EDHF-mediated responses, in response to agonists that stimulate G-protein-coupled receptors, are associated with an increase in [Ca2+]i in the endothelial cell (Fig. 1) 17., 18. and are also generated by substances that increase endothelial [Ca2+]i in a receptor-independent manner (e.g. Ca2+ ionophores, and the sarcoplasmic reticulum Ca2+-ATPase inhibitors thapsigargin and cyclopiazonic acid) 19., 20.. Conversely, a decrease in the extracellular Ca2+ concentration attenuates EDHF responses [21]
Identification of the K+ channels involved in the EDHF pathway
Endothelium-dependent hyperpolarizations (in the presence of inhibitors of NO synthases and cyclooxygenases) are not prevented by glibenclamide [an inhibitor of ATP-dependent K+ (KATP) channels] but are blocked by specific toxins that inhibit Ca2+-sensitive (KCa) K+ channels. Indeed, a hallmark of the EDHF-mediated response, first observed by Garland’s group, is its abolition by the combination of apamin [a specific inhibitor of KCa channels of small conductance (SKCa channels)] plus
Beyond endothelial hyperpolarization
Why have so many vastly different hypotheses been proposed concerning the mechanism of EDHF-mediated responses? Increasing the [Ca2+]i in endothelial cells opens not only SKCa and IKCa channels, which results in the efflux and accumulation of K+ in the myo-endothelial space, but also leads to the activation of various enzymes including phospholipases and the subsequent metabolism of arachidonic acid by cytochrome P450 epoxygenases. Currently, experimental evidence favours three explanations for
Conclusion: bringing the concepts together
There is now good evidence that EDHF-mediated responses are initiated by an increase in the endothelial [Ca2+]i and the consequent activation of endothelial SKCa and IKCa channels, which elicits the hyperpolarization of the endothelial cells (Fig. 2). In some tissues, the hyperpolarization of the endothelial cells might be regulated by the activation of cytochrome P450 and the resulting generation of EETs. The endothelial hyperpolarization could then spread to the adjacent smooth muscle cells
Note added in proof
Recently, a specific antagonist of EETs was synthesized and was shown to further substantiate, in bovine coronary artery, the involvement of cytochrome P450 epoxygenase metabolites in EDHF-mediated responses [81]. However, it is not yet known whether this antagonist targets the endothelial cells or the smooth muscle cells. A transient increase in the level of cAMP might play a permissive role in the EDHF-mediated responses by enhancing the electrotonic spread of endothelial hyperpolarization
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