title: Angiotensin II and myosin light-chain phosphorylation contribute to the stretch-induced slow force response in human atrial myocardium.
abstract: 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.
authors.affiliation: Division of Cardiology, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria.
authors.forename: Jens
authors.initials: J
authors.lastname: Kockskämper
authors.forename: Mounir
authors.initials: M
authors.lastname: Khafaga
authors.forename: Michael
authors.initials: M
authors.lastname: Grimm
authors.forename: Andreas
authors.initials: A
authors.lastname: Elgner
authors.forename: Stefanie
authors.initials: S
authors.lastname: Walther
authors.forename: Anke
authors.initials: A
authors.lastname: Kockskämper
authors.forename: Dirk
authors.initials: D
authors.lastname: von Lewinski
authors.forename: Heiner
authors.initials: H
authors.lastname: Post
authors.forename: Marius
authors.initials: M
authors.lastname: Grossmann
authors.forename: Hilmar
authors.initials: H
authors.lastname: Dörge
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gottlieb
authors.forename: Frederick
authors.initials: F
authors.lastname: Sachs
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Schöndube
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
mesh_terms: 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
chemical_list: 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