Ryanodine and the left ventricular force-interval and relaxation-interval relations in closed-chest dogs: insights on calcium handling.

Academic Article

Abstract

  • 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 micrograms/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.
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    Keywords

  • Analysis of Variance, Animals, Calcium, Calcium Channel Blockers, Dogs, Electrocardiography, Female, Intracellular Fluid, Male, Myocardial Contraction, Myocardium, Ryanodine, Sarcoplasmic Reticulum, Signal Processing, Computer-Assisted, Stroke Volume
  • Author List

  • Prabhu SD
  • Start Page

  • 483
  • End Page

  • 491
  • Volume

  • 40
  • Issue

  • 3