Influence of sarcoplasmic reticulum calcium loading on mechanical and relaxation restitution

• Published in: American journal of physiology. Heart and circulatory physiology 2000-03, Vol.278 (3), p.H958-H963
• Main Authors: Hoit, Brian D, Kadambi, Vivek J, Tramuta, Daniel A, Ball, Nancy, Kranias, Evangelia G, Walsh, Richard A
• Format: Article
• Language: English
• Subjects: Animals; Biomechanical Phenomena; Blood Pressure; Calcium - metabolism; Calcium-Binding Proteins - deficiency; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - physiology; Heart Rate; Mice; Mice, Knockout; Myocardial Contraction - physiology; Ryanodine - pharmacology; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - physiology; Space life sciences
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.2000.278.3.H958

1  Division of Cardiology and 2  Department of Pharmacology and Cell Biophysics, University of Cincinnati Medical Center, Cincinnati 45267-0575; and 3  Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 Mechanical and relaxation restitution represent the restoration of contractile force and relaxation, respectively, in premature beats having progressively longer extrasystolic intervals (ESI); these phenomena are related to intracellular activator Ca 2+ by poorly defined mechanisms. We tested the hypothesis that the level of phospholamban [which modulates the affinity of the sarcoplasmic reticulum (SR) Ca 2+ -ATPase for Ca 2+ , and thus the SR Ca 2+ load] may be an important determinant of both mechanical and relaxation restitution. Five mice with ablation of the phospholamban (PLB) gene (PLBKO), eight isogenic wild-type controls (129SvJ), eleven mice with PLB overexpression (PLBOE), and nine isogenic wild-type (FVB/N) controls were anesthetized and instrumented with a 1.4-Fr Millar catheter in the left ventricle and a 1-Fr pacemaker in the right atrium. At a cycle length of 200 ms, extrastimuli with increasing ESI were introduced, and the peak rates of left ventricular isovolumic contraction (±dP/d t max ) were normalized and fit to monoexponential equations. In a subset, the protocols were repeated after ryanodine (4 ng/g) was administered to deplete SR Ca 2+ stores. The time constant of mechanical restitution in PLBKO was significantly shorter [6.3 ± 1.2 (SE) vs. 47.7 ± 7.6 ms] and began earlier (50 ± 10 vs. 70 ± 19 ms) than in 129SvJ. In contrast, the time constant of mechnical restitution was significantly longer (80.3 ± 7.6 vs. 54.1 ± 9.2 ms) in PLBOE than in FVB/N. The time constant of relaxation restitution was less in PLBKO than in 129SvJ (26.2 ± 9.9 vs. 44.6 ± 3.3,  P