© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Ryanodine and the left ventricular force–interval and relaxation–interval relations in closed-chest dogs: insights on calcium handling
aDepartment of Medicine/Cardiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San AntonioTX 78284-7872, USA
bAudie Murphy Memorial Veterans Hospital, San Antonio TX 78284, USA
* Tel.: +1-(210)-567-4600; fax: +1-(210)-567-6960; e-mail: Prabhu@uthscsa.edu
Objective: Although the myocardial force–interval and relaxation–interval relations are considered to be mechanical expressions of myocardial Ca2+ handling, correlation of these phenomena with altered Ca2+ kinetics in the intact state is limited. Thus, I sought to determine the impact of selective impairment of physiologic sarcoplasmic reticulum Ca2+ release, achieved by the use of the drug ryanodine, on these relations in the intact animal. Methods: Twelve dogs instrumented with left ventricular manometers and piezoelectric dimension crystals were studied before and after ryanodine (4 µg/kg intravenously). End-systolic elastance was measured at paced heart rates of 120–180 bpm to determine the force-frequency response. Mechanical restitution and relaxation restitution were determined by measuring contractile (single beat elastance) and relaxation (peak negative dP/dt) responses for beats delivered at graded extrasystolic intervals, with normalized responses expressed as a function of extrasystolic interval. Results: Ryanodine accelerated mechanical restitution (time constant 60.3±3.9 versus 81.7±10.1 ms, p<0.05) and reduced maximal contractile response (107.5±2.1 versus 122.1±5.7%, p<0.05), slowed early relaxation restitution (time constant 65.5±13.8 versus 36.8±3.8 ms, p<0.05) without changing late relaxation restitution kinetics, and amplified the force-frequency response (end-systolic elastance, 180 bpm, 19.4±4.3 versus 11.4±1.2 mm Hg/ml, p<0.05). Conclusions: These findings suggest that in the intact animal, Ca2+ handling by the sarcoplasmic reticulum is a primary determinant of mechanical restitution and early relaxation restitution, but not late relaxation restitution. Conversely, ryanodine induced augmentation of the force-frequency response indicates a central role for sarcolemmal Ca2+ influx in producing frequency potentiation.
KEYWORDS MR, Mechanical restitution; FFR, Force–frequency response; RR, Relaxation restitution; SR, Sarcoplasmic reticulum; SL, Sarcolemma; LV, Left ventricle, left ventricular; P, Pressure; V, Volume; dAP, Anterior–posterior diameter; dSL, Septal–lateral diameter; dLA, Long axis diameter; ECG, Electrocardiogram; PES–VES, End-systolic pressure–volume; HR, Heart rate; ESI, Extrasystolic interval; VCF, Mean velocity of circumferential fiber shortening; VLV, Left ventricular volume; ED, End-diastole, end-diastolic; ES, End-systole, end-systolic; EES, End-systolic elastance; V0, Volume intercept of end-systolic pressure–volume relation; SW, Stroke work; SBE, Single beat elastance; CRmax, Maximal contractile response; TC, Time constant; ESI0, ESI axis intercept of mechanical restitution curve; TCM, Time constant of mechanical restitution; TCR, Time constant of relaxation restitution; RRmax, Asymptotic plateau of relaxation response
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