EFFECTS OF BRL55834 IN RAT PORTAL-VEIN AND BOVINE TRACHEA - EVIDENCE FOR THE INDUCTION OF A GLIBENCLAMIDE-RESISTANT, ATP-SENSITIVE POTASSIUM CURRENT

1 The effects of the benzopyran K-channel opener, BRL55834, on mechani cal activity in bovine trachealis and rat portal vein were studied tog ether with membrane currents in freshly-isolated single cells derived from these tissues. 2 BRL55834 (3 nM-1 mu M) produced a concentration- dependent relaxation of bovine trachealis precontracted with 100 mu M histamine and reduced the spontaneous mechanical activity of rat porta l veins, effects which were antagonized by glibenclamide (1-10 mu M) b ut were not reversible on washing. In contrast, charybdotoxin (250 nM) did not modify the spasmolytic effect of BRL55834 in bovine tracheali s. 3 BRL55834 (10 nM-10 mu M) did not relax segments of bovine trachea lis precontracted with 80 mM KCI. 4 In some freshly-isolated single ce lls from bovine trachealis held at -10 mV, BRL55834 (3 mu M) induced a time-independent outward K-current which was partially resistant to i nhibition by glibenclamide (10 mu M). In other cells, a very noisy, ou twardly-rectifying and charybdotoxin-sensitive current developed in th e presence of BRL55834 (3 mu M) and in time-matched control cells. 5 I n freshly-isolated single cells from rat portal vein held at -10 mV, B RL55834 (3 mu M) induced a time- and calcium-independent outward K-cur rent which was partially resistant (approximately 25% inhibition at +4 0 mV) to subsequent inhibition by glibenclamide (10 mu M). In contrast , levcromakalim induced a time-independent outward K-current which was completely inhibited by glibenclamide 10 mu M. 6 With the non-hydroly sable ATP analogue, AMP-PCP (5 mM), in the pipette, the ability of BRL 55834 to induce a time-independent K-current in portal vein cells was markedly reduced (approximately 80% inhibition at +40 mV) whereas the effects of 10 mu M levcromakalim were totally inhibited. 7 The glibenc lamide-resistant current component induced by BRL55834 was totally inh ibited by phentolamine (100 mu M), a concentration that had no effect on the peak current (I-BK(Ca)) induced by NS1619 (33 mu M). 8 Stationa ry fluctuation analysis of the noise associated with the glibenclamide -insensitive K-current induced by BRL55834 in rat portal vein cells in dicated that the unitary current flowing through the underlying channe ls was 0.26 pA at -10 mV, a value inconsistent with the involvement of BKCa. 9 It is concluded that the relaxations of both bovine trachea a nd rat portal vein produced by BRL55834 are associated with the openin g of K-channels. These are probably identical to the ATP-sensitive K-c hannel opened by levcromakalim, although the involvement of an additio nal K-channel cannot be excluded. The reduced sensitivity of the BRL55 834-induced changes to glibenclamide and to AMP-PCP may result from av id binding of BRL55834 to its site of action.