Role of KCa Channels in EDHFMediated Dilation

There are three classes of KCa channels, large-

conductance KCa (BKCa), intermediate-conductance K(

(IKCa), and small-conductance KCa (SKCa), named based on their respective unitary channel conductance [2]. The conductances for BKCa, IKCa, and SKCa channels are 200-250 pS, 20-80 pS, and 2-20pS, respectively. All of the channels are activated by Ca2+, though the IKCa and SKCa channels are activated at much lower Ca2+ concentrations than the BKCa channels (250-500 nM versus 1-10 ||M). The channels also differ in that the BKCa channels are voltage sensitive (activated upon depolarization) whereas the IKCa and SKCa channels are voltage insensitive. There are three known isoforms of SKCa channels, SK1, SK2, and SK3, whereas the IKCa channel (IK1) does not have any additional known isoforms.

One of the hallmarks of EDHF-dependent responses is the sensitivity to certain KCa channel inhibitors. For most peripheral arteries, complete inhibition of the response requires combined inhibition of IKCa (charybdotoxin) and SKCa channels (apamin) [3, 4]. In the cerebral circulation, complete inhibition appears only to require inhibition of IKCa channels. Inhibition of the BKCa channels alone (iberi-otoxin) or in combination with SKCa channels does not affect the EDHF-dependent response.

Because charybdotoxin is a nonspecific blocker (inhibits BKCa, IKCa, Kv1.2, Kv1.3), earlier studies inferred the involvement of IKCa channels based on sensitivity to charybdotoxin and lack of sensitivity to iberiotoxin (BKCa selective) or other Kv channel blockers. The recent development and application of apparently IKCa-specific inhibitors (such as TRAM-34) has provided direct confirmation of the critical involvement of IKCa channels in EDHF-mediated responses.

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