Abstract
The possible involvement of different kinases in the alpha(1)-adrenoreceptor (AR)-mediated positive inotropic effect (PIE) was investigated in rat papillary muscle and compared with beta-AR-, endothelin receptor- and phorbol ester-induced changes in contractility. The alpha(1)-AR-induced PIE was not reduced by the inhibitors of protein kinase C (PKC), MAPK (ERK and p38), phosphatidyl inositol 3-kinase, or calmodulin kinase II. However, PKC inhibition attenuated the effect of phorbol 12-myristate 13-acetate (PMA) on contractility. alpha(1)-AR-induced PIE was reduced by approximately 90% during inhibition of myosin light chain kinase (MLCK) by 1-(5-chloronaphthalene-1-sulfonyl)1H-hexahydro-1,4-diazepine (ML-9). Endothelin-induced PIE was also reduced by ML-9, but ML-9 had no effect on beta-AR-induced PIE. The Rho kinase inhibitor Y-27632 also reduced the alpha(1)-AR-induced PIE. The alpha(1)-AR-induced PIE in muscle strips from explanted failing human hearts was also sensitive to MLCK inhibition. alpha(1)-AR induced a modest increase in (32)P incorporation into myosin light chain in isolated rat cardiomyocytes. This effect was eliminated by ML-9. The PIE of alpha(1)-AR stimulation seems to be dependent on MLCK phosphorylation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Azepines / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Carcinogens / pharmacology
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Cardiotonic Agents / pharmacology*
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Endothelin-1 / pharmacology
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Enzyme Inhibitors / pharmacology
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Humans
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins
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Isoproterenol / pharmacology*
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Myocardial Contraction / drug effects
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Myocardial Contraction / physiology
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Myosin Light Chains / antagonists & inhibitors
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Myosin Light Chains / metabolism*
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Papillary Muscles / drug effects
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Papillary Muscles / enzymology*
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Phenylephrine / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Rats
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Receptors, Adrenergic, alpha-1 / metabolism*
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Receptors, Endothelin / metabolism
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Tetradecanoylphorbol Acetate / pharmacology
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rho-Associated Kinases
Substances
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Azepines
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Carcinogens
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Cardiotonic Agents
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Endothelin-1
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Myosin Light Chains
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Phosphoinositide-3 Kinase Inhibitors
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Receptors, Adrenergic, alpha-1
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Receptors, Endothelin
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ML 9
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Phenylephrine
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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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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Isoproterenol
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Tetradecanoylphorbol Acetate