Characterization of the potassium channels involved in EDHF-mediated relaxation in cerebral arteries

摘要

class="enumerated" style="list-style-type:decimal">In the presence of N^G-nitro-L-arginine (L-NOARG, 0.3 mM) and indomethacin (10 μM), the relaxations induced by acetylcholine and the calcium (Ca) ionophore are considered to be mediated by endothelium-derived hyperpolarizing factor (EDHF) in the guinea-pig basilar artery.Inhibitors of adenosine 5′-triphosphate (ATP)-sensitive potassium (K)-channels (KATP; glibenclamide, 10 μM), voltage-sensitive K-channels (KV; dendrotoxin-I, 0.1 μM or 4-aminopyridine, 1 mM), small (SKCa; apamin, 0.1 μM) and large (BKCa; iberiotoxin, 0.1 μM) conductance Ca-sensitive K-channels did not affect the L-NOARG/indomethacin-resistant relaxation induced by acetylcholine.Synthetic charybdotoxin (0.1 μM), an inhibitor of BKCa and KV, caused a rightward shift of the concentration-response curve for acetylcholine and reduced the maximal relaxation in the presence of L-NOARG and indomethacin, whereas the relaxation induced by was not significantly inhibited.A combination of charybdotoxin (0.1 μM) and apamin (0.1 μM) abolished the L-NOARG/indomethacin-resistant relaxations induced by acetylcholine and . However, the acetylcholine-induced relaxation was not affected by a combination of iberiotoxin (0.1 μM) and apamin (0.1 μ class="small-caps">M).Ciclazindol (10 μ class="small-caps">M), an inhibitor of KV in rat portal vein smooth muscle, inhibited the class="small-caps">L-NOARG/indomethacin-resistant relaxations induced by acetylcholine and , and the relaxations were abolished when ciclazindol (10 μ class="small-caps">M) was combined with apamin (0.1 μ class="small-caps">M).Human pial arteries from two out of four patients displayed an class="small-caps">L-NOARG/indomethacin-resistant relaxation in response to substance P. This relaxation was abolished in both cases by pretreatment with the combination of charybdotoxin (0.1 μ class="small-caps">M) and apamin (0.1 μ class="small-caps">M), whereas each toxin had little effect alone.The results suggest that KV, but not KATP and BKCa, is involved in the EDHF-mediated relaxation in the guinea-pig basilar artery. The synergistic action of apamin and charybdotoxin (or ciclazindol) could indicate that both KV and SKCa are activated by EDHF. However, a single type of K-channel, which may be structurally related to KV and allosterically regulated by apamin, could also be the target for EDHF.