Abstract
The translocation mechanisms involved in the alpha1-adrenoceptor-stimulated efflux of the potassium analog 86Rb+ were studied in isolated rat hearts. Phenylephrine (in the presence of a beta-blocker) increased the efflux of 86Rb+ and 42K+, and the Na-K-2Cl (or K-Cl) cotransport inhibitor bumetanide reduced the response by 42 +/- 11%. Furosemide inhibited the response with a lower potency than that of bumetanide. The bumetanide-insensitive efflux was largely sensitive to the K+ channel inhibitor 4-aminopyridine. Inhibitors of the Na+/H+ exchanger or the Na+-K+ pump had no effect on the increased 86Rb+ efflux. The activation of the Na-K-2Cl cotransporter was dependent on the extracellular signal-regulated kinase (ERK) subgroup of the mitogen-activated protein (MAP) kinase family. Phenylephrine stimulation increased ERK activity 3.4-fold. PD-98059, an inhibitor of the ERK cascade, reduced both the increased 86Rb+ efflux and ERK activity. Specific inhibitors of protein kinase C and Ca2+/calmodulin-dependent kinase II had no effect. In conclusion, alpha1-adrenoceptor stimulation increases 86Rb+ efflux from the rat heart via K+ channels and a Na-K-2Cl cotransporter. Activation of the Na-K-2Cl cotransporter is apparently dependent on the MAP kinase pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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4-Aminopyridine / pharmacology
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Adrenergic alpha-1 Receptor Agonists
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Adrenergic beta-Antagonists / pharmacology
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Alkaloids
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Animals
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Benzophenanthridines
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Bumetanide / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Carrier Proteins / drug effects
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Carrier Proteins / metabolism*
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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In Vitro Techniques
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Kinetics
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Male
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Myocardium / metabolism*
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Phenanthridines / pharmacology
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Phenylephrine / pharmacology*
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Potassium Channels / drug effects
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Potassium Channels / physiology
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Protein Kinase C / metabolism
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Rats
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Rats, Wistar
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Receptors, Adrenergic, alpha-1 / physiology*
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Rubidium Radioisotopes / pharmacokinetics
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Sodium-Potassium-Chloride Symporters
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Staurosporine / pharmacology
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Timolol / pharmacology
Substances
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Adrenergic alpha-1 Receptor Agonists
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Adrenergic beta-Antagonists
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Alkaloids
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Benzophenanthridines
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Carrier Proteins
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Enzyme Inhibitors
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Flavonoids
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Phenanthridines
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Potassium Channels
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Receptors, Adrenergic, alpha-1
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Rubidium Radioisotopes
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Sodium-Potassium-Chloride Symporters
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Bumetanide
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Phenylephrine
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Timolol
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4-Aminopyridine
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chelerythrine
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Protein Kinase C
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Staurosporine
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one