Endothelin receptor pathway in human left ventricular myocytes: Relation to contractility

Background. Increased synthesis and release of the potent bioactive peptide endothelin-l (ET-1) occurs during and after cardiac surgery. However, the cellular and molecular basis for the effects of ET-1 on human left ventricu lar (LV) myocyte contractility remains unknown. Methods. LV myocyte contractility was examined from myocardial biopsies tak en from patients (n = 30) undergoing elective coronary artery bypass. LV my ocytes (n = 997, > 30/patient) were isolated using microtrituration and con tractility examined by videomicroscopy at baseline and after ET-1 exposure (200 pmol/L). In additional studies, myocytes were pretreated to inhibit ei ther protein kinase C (PKC) (chelerythrine, 1 mu mol/L), the sodium/hydroge n (Na/H) exchanger (EIPA, 1 mu mol/L), both PKC and the Na/H exchanger, or the ETA receptor (BQ-123, 1 mu mol/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, ETA inhibition demonstrated that ET-1 effects on myocyt e contractility were mediated through the ETA receptor subtype. Conclusions. ET-1 directly influences human LV myocyte contractility, which is mediated through the ETA receptor and requires intracellular activation of PKC and stimulation of the Na/H exchanger. (C) 2000 by The Society of T horacic Surgeons.