Characterization of the endothelin-1-induced regulation of L-type Ca2+ current in rabbit ventricular myocytes

Naunyn Schmiedebergs Arch Pharmacol. 1999 Dec;360(6):654-64. doi: 10.1007/s002109900130.


The effects of endothelin-1 (ET-1) on the L-type Ca2+ current (I(Ca)) and the interaction of ET-1 with beta-adrenoceptor stimulation were investigated in rabbit ventricular myocytes by the whole-cell patch-clamp technique. ET-1 (10(-8) M) had a biphasic effect on I(Ca) (direct effect), causing a transient decrease that was followed by a long-lasting increase which is much smaller than the increase induced by isoprenaline (ISO). The effect of ET-1 on I(Ca) was abolished by a selective ET(A) receptor antagonist, FR139317 (10(-6) M). The increase in I(Ca) induced by ET-1 (10(-8) M) was enhanced by a selective ET(B) receptor antagonist, BQ-788 (10(-6) M), as the transient decrease but not the increase in I(Ca) induced by ET-1 (10(-8) M) was suppressed by BQ-788. In the presence of ISO (10(-6) M), ET-1 elicited a more pronounced inhibitory effect: at 10(-9)-10(-7) M ET-1 inhibited the ISO-induced increase in I(Ca) in a concentration-dependent manner (anti-adrenergic effect). The maximum inhibition induced by ET-1 at 10(-7) M was approximately 80% of the ISO-induced response, and the IC50 value for anti-adrenergic effect of ET-1 was 4.2x10(-9) M. The anti-adrenergic effect of ET-1 (10(-8) M) was antagonized by the ET(A) antagonist FR139317 (10(-9)-10(-6) M) in a concentration-dependent manner and was partially inhibited by the ET(B) antagonist BQ-788 (10(-6) M). The anti-adrenergic effect of ET-1 was markedly attenuated by pretreatment of ventricular myocytes with pertussis toxin. The increases in I(Ca) induced by forskolin (10(-6) M), 3-isobutyl-1-methylxanthine (10(-4) M), and 8-bromo-cyclic AMP (3x10(-4) M) were also suppressed by ET-1 (10(-8) M). In summary, ET-1 has a differential effect on I(Ca) in the absence and in the presence of ISO: ET- I has a feeble biphasic action on the baseline I(Ca) and, in addition, it elicits a pronounced anti-adrenergic effect on the ISO-induced increase in I(Ca). Pertussis toxin-sensitive G protein is responsible for the anti-adrenergic effect of ET-1 on I(Ca), but the anti-adrenergic effect of ET-1 may involve also the regulation at the level of signaling process beyond the cyclic AMP generation. Anti-adrenergic effect of ET-1 on I(Ca) is mainly due to activation of ET(A) receptors but ET(B) receptors are also involved partially in the anti-adrenergic effect of ET-1 on I(Ca) in rabbit ventricular myocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Azepines / pharmacology
  • Calcium / metabolism*
  • Calcium Channels, L-Type / drug effects*
  • Calcium Channels, L-Type / metabolism
  • Cells, Cultured
  • Endothelin Receptor Antagonists
  • Endothelin-1 / antagonists & inhibitors
  • Endothelin-1 / pharmacology*
  • Heart Ventricles / cytology
  • Heart Ventricles / drug effects*
  • Heart Ventricles / metabolism
  • In Vitro Techniques
  • Indoles / pharmacology
  • Isoproterenol / pharmacology
  • Male
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Patch-Clamp Techniques
  • Pertussis Toxin
  • Phosphodiesterase Inhibitors / pharmacology
  • Protein Kinase C / antagonists & inhibitors
  • Rabbits
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Virulence Factors, Bordetella / pharmacology


  • Adrenergic beta-Agonists
  • Azepines
  • Calcium Channels, L-Type
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Indoles
  • Phosphodiesterase Inhibitors
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Virulence Factors, Bordetella
  • FR 139317
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Pertussis Toxin
  • Protein Kinase C
  • Isoproterenol
  • Calcium
  • 1-Methyl-3-isobutylxanthine