Responsiveness of the myofilaments to Ca2+ in human heart failure:implications for Ca2+ and force regulation

R. J. Hajjar, W. Grossman, J. K. Gwathmey

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Myofilament calcium sensitivity and maximal calcium-activated force are fundamental properties of the contractile proteins in the heart. We examined these properties in normal human right-ventricular trabeculae carneae obtained from hearts of brain-dead patients with no known cardiac disease, and from patients with end-stage heart failure undergoing cardiac transplantation. There were no differences in calcium-activation of the control and myopathic muscles from chemically-skinned trabeculae or from intact tetanized preparations. We then tested the effect of DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H- indole-carbonitrile), a new inotropic agent, in both preparations. In myopathic muscles, 1 μM DPI sensitized the myofilaments to Ca2+, as evidenced by a significant shift of the [Ca2+]-force relationship towards lower [Ca2+], in both skinned and intact preparations. On the other hand, the same concentration of DPI did not affect the calcium-activation in control muscles in both preparations. We also found that the twitch [Ca2+]-force relationship, which has been used as an indication of myofilament sensitivity, was dissociated from the steady-state [Ca2+]-force relationship, and was shifted along the [Ca2+] axis by modulation in the time-course of the twitch and [Ca2+](i), and not by the sensitivity of the myofilaments to Ca2+. Protein kinase C stimulation differentially altered the responsiveness of the myofilaments to Ca2+ in normal and myopathic muscle fibers. We propose that even though calcium activation and maximal calcium-activated force are unaltered in myopathic hearts there are changes in thin filament regulation in myopathic hearts that result in altered responses to agents that directly act on the thin filaments, and that the potential for force development is similar in normal and myopathic human hearts.

Original languageEnglish
Pages (from-to)143-159
Number of pages17
JournalBasic Research in Cardiology
Volume87
Issue numberSUPPL. 1
DOIs
StatePublished - 1992
Externally publishedYes

Keywords

  • Calcium
  • Cardiomyopathy
  • Human
  • Myofilaments
  • Protein kinase C

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