Inhibition of alpha-adrenergic responses in the rat liver by lipophilic K+ channel blockers or depolarizing Cl- gradients. Evidence for a potential-sensitive step in the signal transduction path.
To study the role of K+ channels and membrane potential in alpha-adrenergic responses of the rat liver, lipophilic K+ channel blockers quinidine and 4-aminopyridine were used or external Cl- was replaced with gluconate, an impermeant ion. Glucose release, O2 uptake, portal pressure, and K+ flux were measured in the isolated perfused liver. The alpha-agonist phenylephrine caused biphasic changes in each parameter, a fast transient followed by sustained elevated responses. Infusion of 5 mM 4-aminopyridine, 0.1 mM quinidine, or gluconate prior to phenylephrine inhibited each parameter, with the greatest inhibition occurring during the second phase. A similar pattern was seen with 2 mM EGTA. This contrasts with the full inhibition of all responses following exposure to the alpha-antagonist phentolamine. Infusion of each inhibitor at the peak of the sustained phase inhibited all responses. Phenylephrine-stimulated release of K+ was augmented in the presence of EGTA and was inhibited by 4-aminopyridine or quinidine. In contrast, beta-adrenergic stimulation of glucose release and K+ flux were not affected by the K+ channel blockers. Phenylephrine-stimulated glucose release from hepatocyte suspensions decreased by about 50% in the presence of 4-aminopyridine, EGTA, or gluconate. The results are discussed in terms of a potential role for K+ channels in alpha-adrenergic signal transduction in the liver.
Hill
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Department of Biological Sciences, University of Calgary, AB, Canada.
Ajikobi
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D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002712:Chlorides / Q000378:metabolism*; D004492:Edetic Acid / Q000494:pharmacology; D005942:Gluconates / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D010101:Oxygen Consumption; D017082:Portal Pressure; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D002712:Chlorides; D005942:Gluconates; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011942:Receptors, Adrenergic, alpha; D004492:Edetic Acid; D015761:4-Aminopyridine; D011802:Quinidine; D005947:Glucose; C030691:gluconic acid; D011188:Potassium