Angiotensin II and myosin light-chain phosphorylation contribute to the stretch-induced slow force response in human atrial myocardium.
OBJECTIVE
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.


RESULTS
Isometric twitch force of human atrial trabeculae (n = 252) was recorded (37 degrees C, 1 Hz stimulation) following stretch from 88 (L88) to 98% (L98) of optimal length. [Na(+)](i) and pH(i) were measured using SBFI and BCECF epifluorescence, respectively. Stretch induced a biphasic force increase: an immediate increase [first-phase, Frank-Starling mechanism (FSM)] to approximately 190% of force at L88 followed by an additional slower increase [5-10 min; slow force response (SFR)] to approximately 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 approximately 1 mmol/L and pH(i) remained unchanged during the SFR. Inhibition of Na(+)/H(+)-exchange (3 microM HOE642), Na(+)/Ca(2+)-exchange (5 microM KB-R7943), or stretch-activated channels (0.5 microM GsMtx-4 and 80 microM streptomycin) did not reduce the SFR. Inhibition of angiotensin-II (AngII) receptors (5 microM saralasin and 0.5 microM PD123319) or pre-application of 0.5 microM AngII, however, reduced the SFR by approximately 40-60%. Moreover, stretch increased phosphorylation of myosin light chain 2 (MLC2a) and inhibition of MLC kinase (10 microM ML-7 and 5 microM wortmannin) decreased the SFR by approximately 40-85%.


CONCLUSIONS
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 Ca(2+) responsiveness via phosphorylation of MLC2a by MLC kinase.
Kockskämper
Jens
J
Division of Cardiology, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria.
Khafaga
Mounir
M
Grimm
Michael
M
Elgner
Andreas
A
Walther
Stefanie
S
Kockskämper
Anke
A
von Lewinski
Dirk
D
Post
Heiner
H
Grossmann
Marius
M
Dörge
Hilmar
H
Gottlieb
Philip A
PA
Sachs
Frederick
F
Eschenhagen
Thomas
T
Schöndube
Friedrich A
FA
Pieske
Burkert
B
D000804:Angiotensin II / Q000378:metabolism*; D020517:Atrial Appendage / Q000378:metabolism; D024722:Cardiac Myosins / Q000378:metabolism*; D048429:Cell Size; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000378:metabolism; D007537:Isometric Contraction; D007700:Kinetics; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008954:Models, Biological; D053580:Muscle Strength; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D010766:Phosphorylation; D012026:Reflex, Stretch; D015203:Reproducibility of Results; D012504:Saralasin / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
D007473:Ion Channels; D018994:Myosin Light Chains; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; C107184:myosin light chain 2; D000804:Angiotensin II; D012964:Sodium; D009219:Myosin-Light-Chain Kinase; D024722:Cardiac Myosins; D012504:Saralasin