Fropofol decreases force development in cardiac muscle

Xianfeng Ren, William Schmidt, Yiyuan Huang, Haisong Lu, Wenjie Liu, Weiming Bu, Roderic Eckenhoff, Anthony Cammarato, Wei Dong Gao

Research output: Contribution to journalArticle

Abstract

Supranormal contractile properties are frequently associated with cardiac diseases. Anesthetic agents, including propofol, can depress myocardial contraction. We tested the hypothesis that fropofol, a propofol derivative, reduces force development in cardiac muscles via inhibition of cross-bridge cycling and may therefore have therapeutic potential. Force and intracellular Ca2+ concentration ([Ca2+]i) transients of rat trabecular muscles were determined. Myofilament ATPase, actin-activated myosin ATPase, and velocity of actin filaments propelled by myosin were also measured. Fropofol dose dependently decreased force without altering [Ca2+]i in normal and pressure-induced hypertrophied-hypercontractile muscles. Similarly, fropofol depressed maximum Ca2+-activated force (Fmax) and increased the [Ca2+]i required for 50% of Fmax (Ca50) at steady state without affecting the Hill coefficient in both intact and skinned cardiac fibers. The drug also depressed cardiac myofibrillar and actin-activated myosin ATPase activity. In vitro actin sliding velocity was significantly reduced when fropofol was introduced during rigor binding of cross-bridges. The data suggest that the depressing effects of fropofol on cardiac contractility are likely to be related to direct targeting of actomyosin interactions. From a clinical standpoint, these findings are particularly significant, given that fropofol is a nonanesthetic small molecule that decreases myocardial contractility specifically and thus may be useful in the treatment of hypercontractile cardiac disorders.

Original languageEnglish (US)
Pages (from-to)4203-4213
Number of pages11
JournalFASEB Journal
Volume32
Issue number8
DOIs
StatePublished - Aug 2018

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Keywords

  • Excitation contraction coupling
  • Fropofol
  • In vitro motility
  • Intracellular calcium
  • Myofilament protein

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Ren, X., Schmidt, W., Huang, Y., Lu, H., Liu, W., Bu, W., Eckenhoff, R., Cammarato, A., & Gao, W. D. (2018). Fropofol decreases force development in cardiac muscle. FASEB Journal, 32(8), 4203-4213. https://doi.org/10.1096/fj.201701442R