Endocardial endothelium is a key determinant of force-frequency relationship in rat ventricular myocardium

Xiaoxu Shen, Zhen Tan, Xin Zhong, Ye Tian, Xian Wang, Bo Yu, Genaro Ramirez-Correa, Anne Murphy, Kathleen Gabrielson, Nazareno Paolocci, Wei Dong Gao

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


We tested the hypothesis that removing endocardial endothelium (EE) negatively impacts the force-frequency relationship (FFR) of ventricular myocardium and dissected the signaling that underlies this phenomenon. EE of rat trabeculae was selectively damaged by brief (<1 s) exposure to 0.1% Triton X-100. Force, intracellular Ca2+ transient (iCa2+), and activity of protein kinase A (PKA) and protein kinase C (PKC) were determined. In control muscles, force and iCa2+ increased as the stimulation frequency increased in steps of 0.5 Hz up to 3.0 Hz. However, EE-denuded (EED) muscles exhibited a markedly blunted FFR. Neither isoproterenol (ISO; 0.1-5 nmol/l) nor endothelin-1 (ET-1; 10-100 nmol/l) alone restored the slope of FFR in EED muscles. Intriguingly, however, a positive FFR was restored in EED preparations by combining low concentrations of ISO (0.1 nmol/l) and ET-1 (20 nmol/l). In intact muscles, PKA and PKC activity increased proportionally with the increase in frequency. This effect was completely lost in EED muscles. Again, combining ISO and ET-1 fully restored the frequency-dependent rise in PKA and PKC activity in EED muscles. In conclusion, selective damage of EE leads to significantly blunted FFR. A combination of low concentrations of ISO and ET-1 successfully restores FFR in EED muscles. The interdependence of ISO and ET-1 in this process indicates cross-talk between the β1-PKA and ET-1-PKC pathways for a normal (positive) FFR. The results also imply that dysfunction of EE and/or EEmyocyte coupling may contribute to flat (or even negative) FFR in heart failure.

Original languageEnglish (US)
Pages (from-to)383-393
Number of pages11
JournalJournal of applied physiology
Issue number3
StatePublished - Aug 1 2013


  • Cardiac excitation-contraction coupling
  • Endocardial endothelium
  • Endothelin-1
  • Force-frequency relationship
  • Isoproterenol
  • Rat myocardium

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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