Mechanism of EDHFMediated Vasodilatation

Although the proposed mechanism of EDHF-mediated vasodilatation is continually evolving, the following represents a general understanding at this time (see Figure 1). (1)

Figure 1 Cartoon depiction of the role of endothelial cytosolic Ca2+ ([Ca2+]j) in EDHF-mediated vasodilatation. Abbreviations: Endo, endothelial cell; SMC, smooth muscle cell; R, receptor; IK, intermediate-conductance KCa channel; SK, small-conductance KCa channel; VOC, voltage-operated Ca2+ channel; ChTx, charybdotoxin; Apa, apamin. Possible Ca2+-sensitive mechanisms that could modulate the EDHF-dependent mechanism are represented by "?."

Figure 1 Cartoon depiction of the role of endothelial cytosolic Ca2+ ([Ca2+]j) in EDHF-mediated vasodilatation. Abbreviations: Endo, endothelial cell; SMC, smooth muscle cell; R, receptor; IK, intermediate-conductance KCa channel; SK, small-conductance KCa channel; VOC, voltage-operated Ca2+ channel; ChTx, charybdotoxin; Apa, apamin. Possible Ca2+-sensitive mechanisms that could modulate the EDHF-dependent mechanism are represented by "?."

An agonist binds to its receptor on the endothelium. This binding initiates a cascade of events that leads to an elevation of endothelial cytosolic free calcium ([Ca2+]j). Calcium ionophores, such as A23187, have also been demonstrated to initiate EDHF-mediated dilations by producing an increase in endothelial [Ca2+]r (2) Elevated endothelial [Ca2+]j stimulates endothelial calcium-sensitive K channels (KCa) and promotes hyperpolarization of the endothelium. Elevated endothelial [Ca2+] also results in activation of other pathways that may be important modulators of the EDHF-dependent mechanism. (3) The endothelial hyper-polarization then promotes smooth muscle hyperpolariza-tion by a mechanism that is still quite controversial. One of the prevailing ideas is that hyperpolarization is conducted directly via myoendothelial gap junctions, which form electrical couplings between adjacent smooth muscle and endothelial cells. There is pharmacological, electrophysio-logical, and histological evidence in support of such a mechanism. Another idea is that K+ ions extruded from basolateral KCa channels stimulate smooth muscle inwardly rectifying K channels (Kir) and/or Na+/K+-ATPase. A small elevation in extracellular K+ has been shown to stimulate smooth muscle Kir channels and Na+/K+-ATPase, and could thus promote smooth muscle hyperpolarization in this way. Although the evidence in support of the latter mechanism is much less prevalent, it could be partly due to the technical difficulties in measuring K+ in the small intercellular space between endothelial and smooth muscle cells. (4) Smooth muscle hyperpolarization promotes the closure of voltage-operated Ca2+ channels (VOC). The smooth muscle VOCs are inactivated at hyperpolarized membrane potentials and thus significantly reduce smooth muscle Ca2+ influx. The reduced Ca2+ influx combined with Ca2+ extrusion and resequestration results in a reduction in smooth muscle [Ca2+] and subsequent relaxation or vasodilatation.

Although it was initially believed that EDHF-mediated dilations were the result of a transferable factor (similar to NO and PGI2-mediated responses), recent studies suggest otherwise. Instead, it appears much more likely that EDHF-mediated dilations reflect a process by which endothelial hyperpolarization is translated into smooth muscle hyperpo-larization (see previous discussion). For this reason, some investigators have begun referring to the mechanism as endothelium-dependent hyperpolarization (EDH). It should be noted that more than one EDHF-dependent mechanism may exist. For instance, the mechanism in coronary and renal arteries may critically involve the cytochrome P450-dependent production of epoxyeicosatrienoic acids (EETs). For the purpose of this article, however, only the former (and seemingly more prevalent) mechanism will be reviewed.

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