Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function

Am J Physiol Heart Circ Physiol. 2004 Apr;286(4):H1248-57. doi: 10.1152/ajpheart.00599.2003.


Endothelin-1 (ET-1) has acute positive inotropic effects, but consequences of chronically increased ET-1 on contractile function of cardiac myocytes are largely unknown. In the present study, effects of long-term treatment with ET-1 (10 nM) for 5 days on both force development [force of contraction (FOC)] and kinetics of contraction were determined in heart tissue reconstituted from rat cardiac cells. Isometric force was measured in response to cumulative concentrations of Ca(2+) and isoprenaline. ET-1 augmented basal FOC by 64 +/- 11% (P < 0.05), which was associated with a significantly blunted contractile response to Ca(2+) and isoprenaline. Moreover, ET-1 significantly prolonged relaxation (62 +/- 3 vs. 53 +/- 2 ms). Selective ET(A) (BQ-123) and ET(B) receptor blockade (BQ-788) demonstrated that effects of ET-1 on contractile function were mediated through the ET(A) receptor subtype. Effects of ET-1 were prevented by cotreatment with either Ro31-8425, a PKC inhibitor, or dimethylamiloride, an inhibitor of the Na(+)/H(+) exchanger. In contrast to long-term ET-1 treatment, no changes in contractile parameters were observed after ET-1 treatment for 3 h before force measurement. These data suggest that chronic ET-1 stimulation has dual effects on contractility: improvement of basal force but impairment of twitch kinetics and inotropic responsiveness to beta-adrenoceptor stimulation. The signaling pathways involved include ET(A) receptors, PKC, and the Na(+)/H(+) exchanger. The present in vitro findings raise the possibility that ET-1 may exert both adaptive and maladaptive effects in the failing myocardium in which local accumulation of ET-1 is present.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Endothelin-1 / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Fluorescent Antibody Technique
  • Gene Expression Regulation / drug effects
  • Heart Ventricles / cytology
  • Heart Ventricles / drug effects
  • Hemodynamics / drug effects
  • Humans
  • In Vitro Techniques
  • Isometric Contraction / drug effects
  • Kinetics
  • Myocardial Contraction / drug effects*
  • Myocytes, Cardiac / drug effects*
  • Phenylalanine / metabolism
  • Protein Kinase C / antagonists & inhibitors
  • Rats
  • Rats, Wistar
  • Receptor, Endothelin A / drug effects
  • Receptor, Endothelin B / drug effects
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Sodium-Hydrogen Exchangers / antagonists & inhibitors


  • Endothelin-1
  • Enzyme Inhibitors
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Recombinant Proteins
  • Sodium-Hydrogen Exchangers
  • Phenylalanine
  • Protein Kinase C