How Does Elevated Endothelial [Ca2 Produce Vasodilatation

The interpretation of the role of endothelial Ca2+ in EDHF-mediated responses has recently undergone significant revision. At one time, it was widely held that elevated endothelial [Ca2+] served primarily to activate a putative "EDHF synthase" (or to trigger release of a stored EDHF). More recent studies, however, indicate that the essential role of elevated endothelial [Ca2+]i may instead be to promote endothelial hyperpolarization via stimulation of endothelial KCa channels, in particular the IKCa and SKCa channels. This idea is further supported by the fact that the endothelial [Ca2+] required to initiate EDHF-mediated dilations (340 nM Ca2+) falls right within the range of [Ca2+] reported to activate IKCa and SKCa channels (~250-500 nM Ca2+) [2, 7].

The type and location of the KCa channels involved in EDHF-mediated responses is still being worked out. However, recent data points to involvement of IKCa channels alone (cerebral arteries) or in combination with SKCa channels (peripheral arteries) located on the endothelium. Endothelial cells have been demonstrated to possess both IKCa and SKCa channels by pharmacological, electrophysio logical, and molecular techniques. Native endothelial cells do not appear to express BKCa channels. Native smooth muscle cells express BKCa channels as well as certain SKCa channels, but they may not express IKCa channels under normal conditions. From these data, it would appear likely that the KCa channels involved in the EDHF-mediated response are located on the endothelial cells.

Admittedly, activation of KCa channels is not the only outcome of elevated endothelial [Ca2+]r One Ca2+-dependent enzyme that has been demonstrated to be involved in the EDHF-mediated response of some arteries is cytosolic phospholipase A2 (cPLA2). The cPLA2 enzyme is a Ca2+-dependent lipase that catalyzes the hydrolysis of the sn-2 linkage of diacyl glycerophosphates, releasing fatty acids such as arachidonic acid. Significant activation of cPLA2 has been demonstrated at Ca2+ concentrations of 230 to 450 nM, a concentration range that brackets the endothe-lial [Ca2+]i concentration for initiating EDHF-mediated responses. One possible explanation of the cPLA2 dependence of EDHF-mediated dilations in some arteries is simply that arachidonic acid or one or more of its numerous metabolites is the EDHF. In coronary arteries in particular, epoxygenase metabolites of arachidonic acid may act as hyperpolarizing factors. However, an alternative explanation is that arachidonic acid or its metabolites modulate the EDHF-dependent mechanism—but are not the EDHF themselves. For instance, arachidonic acid has been demonstrated to activate endothelial transient receptor potential cation channels (TRPV4), which are capable of carrying inward Ca2+ currents. Thus, one conceivable mechanism could involve cPLA2-dependent release of arachidonic acid, activation of TRPV4 by arachidonic acid, increased Ca2+ influx, and subsequent sustained activation of endothelial IKCa and SKCa channels. In this hypothetical scenario, the sensitivity of the mechanism to cPLA2 inhibition could vary depending on several tissue-specific variables such as TRPV4 channel prevalence, relative contribution of other Ca2+ regulation mechanisms, KCa channel Ca2+ sensitivity, and so on. If one therefore considers that cPLA2 can participate in a modulating role, the degree to which it is able to modulate the EDHF-dependent mechanism could vary considerably between arteries and might thus explain the heterogeneity of effects seen with PLA2 inhibitors. Although the preceding scenario is still hypothetical, it is intended to emphasize the point that a number of EDHF candidate factors should also be considered as potential modulators of endothelial KCa channels—and therefore EDHF-mediated vasodilatation.

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