Endothelin receptor pathway in human left ventricular myocytes: relation to contractility.
BACKGROUND
Increased synthesis and release of the potent bioactive peptide endothelin-1 (ET-1) occurs during and after cardiac surgery. However, the cellular and molecular basis for the effects of ET-1 on human left ventricular (LV) myocyte contractility remains unknown.


METHODS
LV myocyte contractility was examined from myocardial biopsies taken from patients (n = 30) undergoing elective coronary artery bypass. LV myocytes (n = 997, > 30/patient) were isolated using microtrituration and contractility examined by videomicroscopy at baseline and after ET-1 exposure (200 pmol/L). In additional studies, myocytes were pretreated to inhibit either protein kinase C (PKC) (chelerythrine, 1 micromol/L), the sodium/hydrogen (Na/H) exchanger (EIPA, 1 micromol/L), both PKC and the Na/H exchanger, or the ET(A) receptor (BQ-123, 1 micromol/L), followed with ET-1 exposure.


RESULTS
Basal myocyte shortening increased 37.8 +/- 6.3% with ET-1 (p < 0.05). Na/H exchanger, PKC, and dual inhibition all eliminated the effects of ET-1. Furthermore, ET(A) inhibition demonstrated that ET-1 effects on myocyte contractility were mediated through the ET(A) receptor subtype.


CONCLUSIONS
ET-1 directly influences human LV myocyte contractility, which is mediated through the ET(A) receptor and requires intracellular activation of PKC and stimulation of the Na/H exchanger.
Goldberg
A T
AT
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29403, USA.
Bond
B R
BR
Mukherjee
R
R
New
R B
RB
Zellner
J L
JL
Crawford
F A
FA
Spinale
F G
FG
D002478:Cells, Cultured; D006352:Heart Ventricles / Q000166:cytology*; D006801:Humans; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017466:Receptors, Endothelin / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors
D017466:Receptors, Endothelin; D017923:Sodium-Hydrogen Exchangers; D011493:Protein Kinase C