The mechanism of actions of 3-(5 '-(hydroxymethyl-2 '-furyl)-1-benzyl indazole (YC-1) on Ca2+-activated K+ currents in GH(3) lactotrophs

The effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), an a ctivator of soluble guanylyl cyclase, on ionic currents have been assessed in rat pituitary GH(3) lactotrophs. In GH(3) cells bathed in normal Tyrode' s solution, YC-1 (1 mu M) reversibly suppressed the amplitude of the Ca2+-a ctivated K+ current (I-K(Ca)). YC-1 at a concentration above 10 mu M produc ed a biphasic response in the amplitude of I-K(Ca), i.e., an initial decrea se followed by a sustained increase. When the pipette solutions were filled with high EGTA (10 mM), the YC-1-induced stimulatory effect on I-K(Ca) was abolished. Over a similar concentration range, YC-1 also effectively inhib ited the voltage-dependent K+ current (I-K(V)) in GH(3) cells. The IC50 val ue required for the inhibition of I-K(V) by YC-1 was 1 mu M. Unlike YC-1, 8 -bromo cGMP did not inhibit I-K(Ca). However, YC-1 (10 mu M) did not affect the amplitude of L-type Ca2+ current. In the cell-attached configuration, application of YC-1 (10 mu M) to the bath did not change the single-channel conductance of the large-conductance Ca2+-activated K+ (BKCa) channels; ho wever, it did increase the opening probability of BKCa channels. In contras t, in the outside-out configuration, YC-1 (10 mu M) significantly suppresse d the opening probability of BKCa channels. The present study shows dual ef fects of YC-1 on I-K(Ca) in GH, cells. The YC-1-mediated stimulation of I-K (Ca) may result from elevated cytosolic Ca2+, whereas the inhibition of I-K (Ca) and I-K(V) by YC-1 appears to be direct and independent of the activat ion of soluble guanylyl cyclase. Caution thus needs to be used in attributi ng the YC-1-mediated response to the activation of soluble guanylyl cyclase . (C) 2000 Elsevier Science Ltd. All rights reserved.