title: Altered inotropic response of endothelin-1 in cardiomyocytes from rats with isoproterenol-induced cardiomyopathy.
abstract: OBJECTIVE
  The positive inotropic effect of endothelin-1 (ET-1) on normal myocardial contraction may be altered in pathological states. The purpose of this study was to assess the direct effect of ET-1 on cardiomyocyte performance and its cellular mechanism in congestive heart failure (CHF).
  
  
  METHODS
  We measured the plasma levels of ET-1 and compared the effects of ET-1 (10(-10)-10(-8) M) on contractile performance and the [Ca2+]i transient in the myocytes of left ventricles (LV) from 15 age-matched normal adult rats and 15 rats with isoproterenol (ISO)-induced CHF.
  
  
  RESULTS
  With CHF, the plasma levels of ET-1 (19.7 +/- 6.3 vs. 4.1 +/- 0.5 fmol/ml, p < 0.05) were markedly elevated. In normal myocytes, superfusion of ET-1 caused significant increases in the systolic amplitude (SA, 8-16%) and the peak velocity of shortening (dL/dtmax, 20-35%; p < 0.01) without causing a change in the peak [Ca2+]i transient. In contrast, in myocytes from CHF rats, ET-1 produced significant reductions in SA (9-13%) and in the velocity of relengthening, dR/dtmax (10-14%; p < 0.05). The myocytes' dR/dtmax also decreased by 8-10% (p < 0.05). These changes were associated with a significant decrease in the peak [Ca2+]i transient (20-23%, p < 0.01). These responses to ET-1 were abolished by the incubation of myocytes with an ETA receptor antagonist (BQ123) or a protein kinase C (PKC) inhibitor (H-7 or staurosporine).
  
  
  CONCLUSIONS
  ISO-induced CHF is associated with elevated plasma ET-1 and an altered cardiomyocyte response to ET-1. After CHF, ET-1 produces a direct depression of cardiomyocyte contractile performance that is associated with a significant decrease in the peak [Ca2+]i transient. These effects are likely to be mediated through ETA receptors and involve the PKC pathway.
authors.affiliation: Cardiology Section, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1045, USA.
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: N
authors.initials: N
authors.lastname: Ohte
authors.forename: Z M
authors.initials: ZM
authors.lastname: Wang
authors.forename: D L
authors.initials: DL
authors.lastname: Williams
authors.forename: W C
authors.initials: WC
authors.lastname: Little
authors.forename: C P
authors.initials: CP
authors.lastname: Cheng
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000097:blood / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D019311:Staurosporine; D007545:Isoproterenol; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium; C039614:ethylisopropylamiloride