Exogenous effects and endogenous production of endothelin in cardiac myocytes: relation to contractile function with congestive heart failure. Thomas, Patrick B., Eddie C. K. Liu, Maria L. Webb, Rupak Mukherjee, Latha Hebbar, Francis G. Spinale. Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina and BMS-Research Institute, Princeton, New Jersey
APStracts 3:0254H, 1996.
Increased plasma concentrations of endothelin have been identified in patients and animals with severe congestive heart failure (CHF). However, whether and to what extent elevated endothelin concentrations directly influence left ventricular (LV) myocyte contractility, endothelin receptor subtype density and endogenous endothelin production with CHF remains unknown. Accordingly, the present project tested the hypothesis that elevated plasma endothelin levels which occur in CHF will be associated with changes in myocyte inotropic responsiveness and endogenous endothelin production. Myocyte contractile function, response to endothelin-1, sarcolemmal endothelin receptor density and myocyte endothelin production were examined in pigs following the development of supraventricular pacing tachycardia (SVT) induced CHF (SVT-CHF; 240 bpm, 3 weeks, n = 8), and in controls (n = 8). With chronic SVT-CHF, LV fractional shortening fell 61%, end-diastolic dimension increased 57% and plasma endothelin levels increased by over three-fold compared to controls. Steady state myocyte shortening velocity was diminished with SVT-CHF compared to controls (25.0 +/- 2.1 vs. 63.7 +/- 1.7 [mu]m/s, respectively; p&LT0.05). In the presence of endothelin-1 (10-500 pM), control myocyte contractile performance increased from baseline in a dose dependent manner, but a dose dependent negative effect occurred with SVT-CHF. For example, in the presence of 200 pM endothelin-1, myocyte shortening velocity increased from baseline by 32.8 +/- 2.3 [mu]m/s in controls, but decreased from baseline by 8.3 +/- 2.2 [mu]m/s in SVT-CHF myocytes. LV sarcolemmal endothelin receptor density was primarily of the ETA receptor subtype in controls (96 +/- 1.0%) and was unchanged with SVT-CHF. In quiescent myocyte preparations maintained in serum free media, control myocytes secreted endothelin at a rate of 2.29 +/- 0.45 amol/cell/hr, and was similar in SVT-CHF myocytes, 2.53 +/- 0.48 amol/cell/hr. In conclusion, the present study demonstrated that exogenous endothelin produced different effects on myocyte contractile function with the development of CHF and these effects are mediated predominately by the ETA receptor subtype. Furthermore, normal and CHF myocytes have the capacity to synthesize abundant endothelin. These findings suggest that increased endothelin production in the setting of CHF may have important effects on LV and myocyte contractile function. 

Received 4 March 1996; accepted in final form 31 May 1996.
APS Manuscript Number H206-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 4 July 96