Alpha1-adrenergic activation of myocardial Na-K-2Cl cotransport involving mitogen-activated protein kinase.
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.
Department of Pharmacology, University of Oslo, N-0316 Oslo, Norway.
G O
GO
Andersen
M
M
Enger
G H
GH
Thoresen
T
T
Skomedal
J B
JB
Osnes
D015761:4-Aminopyridine / Q000494:pharmacology; D058646:Adrenergic alpha-1 Receptor Agonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D002034:Bumetanide / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D012414:Rubidium Radioisotopes / Q000493:pharmacokinetics; D028021:Sodium-Potassium-Chloride Symporters; D019311:Staurosporine / Q000494:pharmacology; D013999:Timolol / Q000494:pharmacology
D058646:Adrenergic alpha-1 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D000470:Alkaloids; D053119:Benzophenanthridines; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010617:Phenanthridines; D015221:Potassium Channels; D018340:Receptors, Adrenergic, alpha-1; D012414:Rubidium Radioisotopes; D028021:Sodium-Potassium-Chloride Symporters; D002034:Bumetanide; D010656:Phenylephrine; D013999:Timolol; D015761:4-Aminopyridine; C016299:chelerythrine; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019311:Staurosporine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one