INHIBITION OF ALPHA-ADRENERGIC RESPONSES IN THE RAT-LIVER BY LIPOPHILIC K(- GRADIENTS - EVIDENCE FOR A POTENTIAL-SENSITIVE STEP IN THE SIGNAL-TRANSDUCTION PATH() CHANNEL BLOCKERS OR DEPOLARIZING CL)

To study the role of K+ channels and membrane potential in alpha-adren ergiC responses of the rat liver, lipophilic K+ channel blockers quini dine and 4-aminopyridine were used or external Cl- was replaced with g luconate, an impermeant ion. Glucose release, O2 uptake, portal pressu re, and K+ flux were measured in the isolated perfused liver. The alph a-agonist phenylephrine caused biphasic changes in each parameter, a f ast transient followed by sustained elevated responses. Infusion of 5 mM 4-aminopyridine, 0.2 mM quinidine, or gluconate prior to phenylephr ine inhibited each parameter, with the greatest inhibition occurring d uring the second phase. A similar pattern was seen with 2 mM EGTA. Thi s contrasts with the full inhibition of all responses following exposu re to the alpha-antagonist phentolamine. Infusion of each inhibitor at the peak of the sustained phase inhibited all responses. Phenylephrin e-stimulated release of K+ was augmented in the presence of EGTA and w as inhibited by 4-aminopyridine or quinidine. In contrast, beta-adrene rgic stimulation of glucose release and K+ flux were not affected by t he K+ channel blockers. Phenylephrine-stimulated glucose release from hepatocyte suspensions decreased by about 50% in the presence of 4-ami nopyridine, EGTA, or gluconate. The results are discussed in terms of a potential role for K+ channels in alpha-adrenergic signal transducti on in the liver.