A number of studies have been performed to evaluate the relationship between endothelial membrane potential (Vm) and endothelial [Ca2+]r The bulk of these studies have been performed with cultured endothelial cells while only a handful of studies have evaluated the relationship in endothelium from intact arteries. In cultured endothelial cells, Ca2+ influx has been shown to be notably modulated by endothelial Vm. As the endothelial cell becomes more hyperpolarized, the driving force for Ca2+ entry is increased and greater Ca2+ influx results following agonist stimulation . If this relationship were to hold true for endothelium within intact arteries, then one possible effect of stimulating endothelial KCa channels (and thus hyperpolarizing the endothelium) would be to promote greater Ca2+ influx in response to EDHF-dependent agonists. In this scenario, the effect of KCa channel blockers on the EDHF-mediated response could be to prevent endothelial [Ca2+] from reaching a critical threshold. However, from the few studies that have addressed this issue in intact arteries, the relationship between endothelial Vm and endothelial [Ca2+] is uncertain. When high K+ has been used to nonselectively inhibit all K+ channels, agonist-mediated increases in endothelial [Ca2+] were shown to be either reduced [9, 10] or unaltered . However, when charybdotoxin plus apamin was administered to block the KCa channels, agonist-mediated increases in endothelial [Ca2+] were shown to be undiminished, despite complete inhibition of the EDHF-mediated relaxation/dilation [9, 11] (see Figure 4). These findings support the conclusion that the essential role of endothelial KCa channels is not to promote or maintain adequate Ca2+ entry for EDHF-mediated dilation. Instead, the essential role of the endothelial KCa channels appears to be to produce endothelial hyperpolarization, entirely downstream of endothelial Ca2+, and thus promote smooth muscle hyper-polarization more directly. This conclusion is supported by a study by Marrelli et al. in which an IKCa channel agonist (1-EBIO) was administered selectively to the endothelium in intact pressurized cerebral arteries . 1-EBIO produced significant hyperpolarization of the endothelium and vasodilatation despite no change in endothelial [Ca2+]r Thus, endothelium-dependent hyperpolarization of the smooth muscle can be produced without any elevation of endothe-lial [Ca2+]j if endothelial KCa channels are activated by some other means. Taken as a whole, it appears that the primary role of endothelial Ca2+ in the EDHF-dependent mechanism may be that of the principal physiological activator of the IKCa and SKCa channels.
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