23. THE ENDOTHELIN RECEPTOR PATHWAY IN HUMAN LV MYOCYTES AND RELATION TO CONTRACTILITY
Aron T. Goldberg, Brian R. Bond, Rupak Mukherjee, R. Brent New, James L. Zellner*, Fred A. Crawford, Jr.*, Francis G. Spinale
CT Surgery, Division of CardioThoracic Surgery, Medical University of South Carolina
Charleston, South Carolina, USA
BACKGROUND
Increased synthesis and release of the potent bioactive peptide endothelin-1 (ET) occurs during and after cardiac surgery. However, the cellular and molecular basis for the effects of ET on human LV myocyte contractility remains unknown. Accordingly, LV myocyte contractility was examined from myocardial biopsies taken from patients undergoing elective CABG (n=30).
METHODS AND RESULTS
LV myocytes (n=997, >30/pt) were isolated using microtrituration and contractility examined by high-speed videomicroscopy at baseline and after ET exposure (200pM). Basal myocyte shortening was 2.59
± 0.05% and increased with ET [Figure; *P<0.05]. In a second set of studies, myocytes were pretreated with either sodium/hydrogen exchange inhibition (Na/Hi; EIPA, 1 m M), protein kinase C inhibition (PKCi; chelerythrine, 1 m M), dual Na/Hi and PCKi, or ETA receptor blockade (ETAi; BQ-123, 1m M), and then followed with ET exposure. Na/Hi, PKCi, and dual treatment all eliminated the effect of ET [Figure; +P<0.05]. Further, ETAi demonstrated that the effect of ET on myocyte contractility was mediated through the ETA receptor subtype.CONCLUSION
The synthesis of ET which occurs in patients perioperatively can directly affect myocyte contractility. Furthermore, the present study uncovered unique cellular and molecular targets by which to modulate this response.
(bar chart)
