CHARACTERIZATION OF THE POTASSIUM CHANNELS INVOLVED IN EDHF-MEDIATED RELAXATION IN CEREBRAL-ARTERIES

1 In the presence of N-G-nitro-L-arginine (L-NOARG, 0.3 mM) and indome thacin (10 mu M), the relaxations induced by acetylcholine and the cal cium (Ca) ionophore A23187 are considered to be mediated by endotheliu m-derived hyperpolarizing factor (EDHF) in the guinea-pig basilar arte ry. 2 Inhibitors of adenosine 5'-triphosphate (ATP)-sensitive potassiu m (K)-channels (K-ATP; glibenclamide, 10 mu M), voltage-sensitive K-ch annels (K-V; dendrotoxin-I, 0.1 mu M or 4-aminopyridine, 1 mM), small (SKCa; apamin, 0.1 mu M) and large (BKCa; iberiotoxin, 0.1 mu M) condu ctance Ca-sensitive K-channels did not affect the L-Noarg/indomethacin -resistant relaxation induced by acetylcholine. 3 Synthetic charybdoto xin (0.1 mu M), an inhibitor of BKCa and K-V, caused a rightward shift of the concentration-response curve for acetylcholine and reduced the maximal relaxation in the presence of L-NOARG and indomerhacin, where as the relaxation induced by A23187 was not significantly inhibited. 4 A combination of charybdotoxin (0.1 mu M) and apamin (0.1 mu M) aboli shed the L-NOARG/indomethacin-resistant relaxations induced by acetylc holine and A23187. However; the acetylcholine-induced relaxation was n ot affected by a combination of iberiotoxin (0.1 mu M) and apamin (0.1 mu M). 5 Ciclazindol (10 mu M). an inhibitor of K-V in rat portal vei n smooth muscle, inhibited the L-NOARG/indomethacin-resistant relaxati ons induced by acetylcholine and A23187, and the relaxations were abol ished when ciclazindol (10 mu M) was combined with apamin (0.1 mu M). 6 Human pial arteries from two out of four patients displayed an L-NOA RG/indomethacin-resistant relaxation in response to substance P. This relaxation was abolished in both cases by pretreatment with the combin ation of charybdotoxin (0.1 mu M) and apamin (0.1 mu M)1 whereas each toxin had little effect alone, 7 The results suggest that K-V, but not L(ATP), and BKCa, is involved in the EDHF-mediated relaxation in the guinea-pig basilar artery. The synergistic action of apamin and charyb dotoxin (or ciclazindol) could indicate that both Ky and SKCa are acti vated by EDHF. However, a single type of K-channel, which may be struc turally related to K, and allosterically regulated by apamin could als o be the target for EDHF.