Published online before print June 2, 2005, doi: 10.1161/01.RES.0000172544.56818.54
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Submitted on December 27, 2004
Revised on May 9, 2005
Accepted on May 24, 2005
Spatial Nonuniformity of Excitation-Contraction Coupling Causes Arrhythmogenic Ca2+ Waves in Rat Cardiac Muscle
Yuji Wakayama ;
From the First Department of Internal Medicine (Y.W., M.M.), Tohoku University, School of Medicine, Sendai, Japan; the Departments of Medicine, Physiology, and Biophysics (B.D.S., H.E.D.J.t.K.), Health Sciences Centre, University of Calgary, Canada; and the Department of Pharmacology (P.A.B.), Columbia University, New York.
* To whom correspondence should be addressed. E-mail: terkeurs{at}ucalgary.ca.
Ca2+ waves underlying triggered propagated contractions (TPCs) are initiated in damaged regions in cardiac muscle and cause arrhythmias. We studied Ca2+ waves underlying TPCs in rat cardiac trabeculae under experimental conditions that simulate the functional nonuniformity caused by local mechanical or ischemic local damage of myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small jet of solution with a composition that reduces excitation-contraction coupling (ECC) in myocytes within that segment. The jet solution contained either caffeine (5 mmol/L), 2,3-butanedione monoxime (BDM; 20 mmol/L), or low Ca2+ concentration ([Ca2+]; 0.2mmol/L). Force was measured with a silicon strain gauge and sarcomere length with laser diffraction techniques in 15 trabeculae. Simultaneously, [Ca2+]i was measured locally using epifluorescence of Fura-2. The jet of solution was applied perpendicularly to a small muscle region (200 to 300 µm) at constant flow. When the jet contained caffeine, BDM, or low [Ca2+], during the stimulated twitch, muscle-twitch force decreased and the sarcomeres in the exposed segment were stretched by shortening normal regions outside the jet. Typical protocols for TPC induction (7.5s-2.5Hz stimulus trains at 23°C; [Ca2+]o=2.0mmol/L) reproducibly generated Ca2+ waves that arose from the border between shortening and stretched regions. Such Ca2+ waves started during force-relaxation of the last stimulated twitch of the train and propagated (0.2 to 2.8 mm/sec) into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were induced when the amplitude of the Ca2+-wave was increased by raising [Ca2+]o. Arrhythmias disappeared rapidly when uniformity of ECC throughout the muscle was restored by turning the jet off. These results show, for the first time, that nonuniform ECC can cause Ca2+ waves underlying TPCs and suggest that Ca2+ dissociated from myofilaments plays an important role in the initiation of Ca2+ waves.
Key words: rat trabeculae • nonuniformity • troponin C • Ca2+ waves • arrhythmias
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