Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 24, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn126
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Angiotensin II and myosin light chain phosphorylation contribute to the stretch-induced slow force response in human atrial myocardium
1 Division of Cardiology, Medical University of Graz, 8036 Graz, Austria
2 Department of Cardiology and Pneumology, University Medicine Göttingen, Germany
3 Department of Thoracic and Cardiovascular Surgery, University Medicine Göttingen, Germany
4 Department of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
5 Department of Physiology and Biophysics, State University of New York at Buffalo, USA
Corresponding author: Prof. Dr. Burkert Pieske Division of Cardiology, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria Phone: +43-316-385-2544; Fax: +43-316-385-3733 Email: burkert.pieske{at}meduni-graz.at
Aim: Stretch is an important regulator of atrial function. The functional effects of stretch on human atrium, however, are poorly understood. Thus, we characterized the stretch-induced force response in human atrium and evaluated the underlying cellular mechanisms.
Methods: Isometric twitch force of human atrial trabeculae (n = 252) was recorded (37°C, 1 Hz stimulation) following stretch from 88% (L88) to 98% (L98) of optimal length. [Na+]i and pHi were measured using SBFI and BCECF epifluorescence, respectively.
Results: Stretch induced a biphasic force increase: an immediate increase (1st-phase, Frank-Starling mechanism, FSM) to 
190% of force at L88 followed by an additional slower increase (5-10 min; slow force response, SFR) to 120% of the FSM. FSM and SFR were unaffected by gender, age, ejection fraction, and pre-medication with major cardiovascular drugs. There was a positive correlation between the amplitude of the FSM and the SFR. [Na+]i rose by 1 mmol/L and pHi remained unchanged during the SFR. Inhibition of Na+/H+-exchange ( 3 µM HOE642), Na+/Ca2+-exchange (5 µM KB-R7943) or stretch-activated-channels (0.5 µM GsMtx-4, 80 µM streptomycin) did not reduce the SFR. Inhibition of angiotensin-II-receptors (5 µM saralasin, 0.5 µM PD123319) or pre-application of 0.5 µM angiotensin-II, however, reduced the SFR by 40-60%. Moreover, stretch increased phosphorylation of myosin-light-chain-2 (MLC2a) and inhibition of MLC-kinase (10 µM ML-7, 5 µM wortmannin) decreased the SFR by 40-85%.
Conclusions: Stretch elicits a SFR in human atrium. The atrial SFR is mediated by stretch-induced release and autocrine/paracrine actions of angiotensin-II and increased myofilament Ca2+ responsiveness via phosphorylation of MLC2a by MLC kinase.
Time for primary review: 37 days
# These authors contributed equally.
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