Cardiovascular Research Advance Access originally published online on May 24, 2008
Cardiovascular Research 2008 79(4):642-651; 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, Auenbruggerplatz 15, A-8036 Graz, Austria
2 Department of Cardiology and Pneumology, University Medicine Göttingen, Göttingen, Germany
3 Department of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
4 Department of Thoracic and Cardiovascular Surgery, University Medicine Göttingen, Göttingen, Germany
5 Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY, USA
* Corresponding author.Tel: +43 316 385 2544; fax: +43 316 385 3733. E-mail address: burkert.pieske{at}meduni-graz.at
Aims: 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 and results: 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. Stretch induced a biphasic force increase: an immediate increase [first-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 and 80 µM streptomycin) did not reduce the SFR. Inhibition of angiotensin-II (AngII) receptors (5 µM saralasin and 0.5 µM PD123319) or pre-application of 0.5 µM AngII, 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 and 5 µM wortmannin) decreased the SFR by 40–85%.
Conclusion: Stretch elicits a SFR in human atrium. The atrial SFR is mediated by stretch-induced release and autocrine/paracrine actions of AngII and increased myofilament Ca2+ responsiveness via phosphorylation of MLC2a by MLC kinase.
KEYWORDS Stretch; Human; Atrium; Force; Angiotensin II
Time for primary review: 37 days
These authors contributed equally.
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