title: Endocardial endothelium is a key determinant of force-frequency relationship in rat ventricular myocardium.
abstract: 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 Ca(2+) transient (iCa(2+)), and activity of protein kinase A (PKA) and protein kinase C (PKC) were determined. In control muscles, force and iCa(2+) 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 EE-myocyte coupling may contribute to flat (or even negative) FFR in heart failure.
authors.affiliation: Cardiology Department, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Shen
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tan
authors.forename: Xin
authors.initials: X
authors.lastname: Zhong
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.forename: Genaro
authors.initials: G
authors.lastname: Ramirez-Correa
authors.forename: Anne
authors.initials: A
authors.lastname: Murphy
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gabrielson
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: Wei Dong
authors.initials: WD
authors.lastname: Gao
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004558:Electric Stimulation; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D056966:Excitation Contraction Coupling / Q000502:physiology; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D006352:Heart Ventricles; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D014129:Trabecular Meshwork / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D019332:Endothelin-1; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D007545:Isoproterenol; D002118:Calcium
keywords: cardiac excitation-contraction coupling; endocardial endothelium; endothelin-1; force-frequency relationship; isoproterenol; rat myocardium