ANTAGONISM OF LEVCROMAKALIM BY IMIDAZOLINE-DERIVATIVES AND GUANIDINE-DERIVATIVES IN RAT PORTAL-VEIN - INVOLVEMENT OF THE DELAYED RECTIFIER

1 In rat whole portal veins, guanabenz (100 nm to 10 muM) and antazoli ne (100 nm to 100 muM) each increased the amplitude, frequency and dur ation of spontaneous contractions. In addition, guanabenz (30 muM) and antazoline (30 muM) each antagonized the ability of levcromakalim (3 nm to 10 muM) to inhibit the spontaneous contractions of this tissue. 2 Whole-cell voltage-clamp recordings were made from freshly-isolated rat portal vein cells dispersed by a collagenase/pronase enzyme treatm ent. The ability of several agents (antazoline, cirazoline, clonidine, guanabenz and phentolamine, each containing an imidazoline or guanidi ne moiety), to modulate potassium (K) currents and to inhibit the acti ons of levcromakalim was investigated. 3 Antazoline, cirazoline, cloni dine, guanabenz and phentolamine (each at a concentration of 30 muM) h ad little effect on-control non-inactivating currents but inhibited th e delayed-rectifier current, I(K(V)). 4 Leveromakalim (1 muM) induced a non-inactivating current, I(K(ATP)), and also inhibited the delayed rectifier current, I(K(V)). 5 Glibenclamide (I muM) had no effect on c ontrol delayed rectifier or non-inactivating currents, but it inhibite d the simultaneous induction of I(K(ATP)) and reduction of I(K(V)) pro duced by levcromakalim (1 muM). 6 Antazoline, cirazoline, clonidine an d guanabenz (each at a concentration of 30 muM) prevented the inductio n of I(K(ATP)) by levcromakalim (1 muM). Phentolamine (30 muM) and clo nidine (30 muM) each inhibited the I(K(ATP)) generated by levcromakali m (1 muM). 7 It is concluded that a variety of agents which possess ei ther an imidazoline (antazoline, cirazoline, clonidine and phentolamin e) or a guanidine (guanabenz) moiety within their structure inhibit th e delayed rectifier current, I(K(v)). This action may thus be mediated via a so-called non-adrenoceptor imidazoline binding site. Furthermor e, the ability of these ligands to inhibit I(K(V)) and to antagonize b oth the induction of I(K(ATP)) and the vasorelaxation produced by levc romakalim is consistent with the view that the channel (K(ATP)) which underlies I(K(ATP)) is a voltage-insensitive state of the delayed rect ifier K-channel (K(V)).