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Cardiovasc Res. 2005 Jan 1;65(1):211-20.

Key role of myosin light chain (MLC) kinase-mediated MLC2a phosphorylation in the alpha 1-adrenergic positive inotropic effect in human atrium.

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  • 1Institute of Experimental and Clinical Pharmacology, University Hospital Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

Abstract

OBJECTIVE:

Mechanisms of the positive inotropic response to alpha(1)-adrenergic stimulation in the heart remain poorly understood, but recent evidence in rat papillary muscle suggests an important role of regulatory myosin light chain (MLC2) phosphorylation. This study investigated alpha(1)-adrenergic contractile effects and the role of MLC kinase (MLCK)-dependent phosphorylation of MLC2 in human atrial muscle strips.

METHODS:

Force measurement was performed on electrically stimulated atrial muscle strips (n=140; 20 hearts) in the presence of the beta-blocker nadolol. MLC2a phosphorylation was determined by 2D-polyacrylamide gel electrophoresis and Western blotting of muscle strips that were immediately freeze-clamped following force measurements.

RESULTS:

The alpha(1)-agonist phenylephrine (PE; 0.3-100 microM) exerted a concentration-dependent, monophasic, sustained positive inotropic effect (86% above basal) that was accompanied by an 80% increase in MLC2a phosphorylation. Desinhibition of MLC phosphatase by the Rho kinase inhibitor Y-27632 (10 microM) reduced the effect of PE by 16%. The MLCK inhibitor wortmannin (10 microM) completely abolished both the PE-induced increase in force and MLC2a phosphorylation. The structurally unrelated MLCK inhibitor ML-7 (10 microM) had similar effects. Neither Y-27632 nor wortmannin or ML-7 affected beta-adrenergic force stimulation. In contrast to our findings in atrial muscle strips, we observed no increase in MLC2v phosphorylation after PE in human ventricular muscle strips and wortmannin failed to inhibit PE-induced force of contraction.

CONCLUSION:

alpha(1)-Adrenergic receptors mediate a prominent increase in contractile force in human atria that depends on MLCK activity and is accompanied by an increase in MLC2 phosphorylation.

PMID:
15621049
[PubMed - indexed for MEDLINE]
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