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Endothelin receptor pathway in human left ventricular myocytes: relation to contractility
A T Goldberg1, B R Bond, R Mukherjee
1Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29403, USA.
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.