title: Role of sarcomere mechanics and Ca2+ overload in Ca2+ waves and arrhythmias in rat cardiac muscle.
abstract: Ca(2+) release from the sarcoplasmic reticulum (SR) depends on the sarcoplasmic reticulum (SR) Ca(2+) load and the cytosolic Ca(2+) level. Arrhythmogenic Ca(2+) waves underlying triggered propagated contractions arise from Ca(2+) overloaded regions near damaged areas in the cardiac muscle. Ca(2+) waves can also be induced in undamaged muscle, in regions with nonuniform excitation-contraction (EC) coupling by the cycle of stretch and release in the border zone between the damaged and intact regions. We hypothesize that rapid shortening of sarcomeres in the border zone during relaxation causes Ca(2+) release from troponin C (TnC) on thin filaments and initiates Ca(2+) waves. Elimination of this shortening will inhibit the initiation of Ca(2+) waves, while SR Ca(2+) overload will enhance the waves. Force, sarcomere length (SL), and [Ca(2+)](i) were measured and muscle length was controlled. A small jet of Hepes solution with an extracellular [Ca(2+)] 10 mM (HC), or HC containing BDM, was used to weaken a 300 mum long muscle segment. Trains of electrical stimuli were used to induce Ca(2+) waves. The effects of small exponential stretches on triggered propagatory contraction (TPC) amplitude and propagation velocity of Ca(2+) waves (V(prop)) were studied. Sarcomere shortening was uniform prior to activation. HC induced spontaneous diastolic sarcomere contractions in the jet region and attenuated twitch sarcomere shortening; HC+ butanedione monoxime (BDM) caused stretch only in the jet region. Stimulus trains induced Ca(2+) waves, which started inside the HC jet region during twitch relaxation. Ca(2+) waves started in the border zone of the BDM jet. The initial local [Ca(2+)](i) rise of the waves by HC was twice that by BDM. The waves propagated at a V(prop) of 2.0 +/- 0.2 mm/sec. Arrhythmias occurred frequently in trabeculae following exposure to the HC jet. Stretch early during relaxation, which reduced sarcomere shortening in the weakened regions, substantially decreased force of the TPC (F(TPC)) and delayed Ca(2+) waves, and reduced V(prop) commensurate with the reduction F(TPC). These results are consistent with the hypothesis that Ca(2+) release from the myofilaments initiates arrhythmogenic propagating Ca(2+) release. Prevention of sarcomere shortening, by itself, did not inhibit Ca(2+) wave generation. SR Ca(2+) overload potentiated initiation and propagation of Ca(2+) waves.
authors.affiliation: School of Medicine, Department of Physiology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada. terkeurs@ucalgary.ca
authors.forename: Henk E D J
authors.initials: HE
authors.lastname: ter Keurs
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wakayama
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Sugai
authors.forename: Guy
authors.initials: G
authors.lastname: Price
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kagaya
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Boyden
authors.forename: Masahito
authors.initials: M
authors.lastname: Miura
authors.forename: Bruno D M
authors.initials: BD
authors.lastname: Stuyvers
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D012518:Sarcomeres / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D002118:Calcium