Exogenous effects and endogenous production of endothelin in cardiac myocytes: potential significance in heart failure

Abstract

Increased plasma concentrations of endothelin have been identified in patients and animals with severe congestive heart failure (CHF). However, whether and to what extent increased endothelin (ET) concentrations influence left ventricular (LV) myocyte contractility, ET-receptor subtype density, and endogenous ET production with the development of CHF remains unclear. Accordingly, myocyte contractile function, response to ET, sarcolemmal ET-receptor density, and myocyte ET production were examined in pigs following the development of pacing-induced CHF (240 beats/min, 3 wk, n = 8) and in controls (n = 8). With CHF, plasma ET increased over threefold. In the presence of ET (10-500 pM), myocyte contractility increased in a dose-dependent manner in control myocytes but decreased in CHF myocytes. For example, in the presence of 200 pM ET, velocity of shortening increased by 32.8 +/- 2.3 microns/s in controls but decreased by 8.3 +/- 2.2 microns/s with CHF. LV sarcolemmal ET-receptor density was primarily of the ETA-receptor subtype in controls (96 +/- 1.0%) and was unchanged with CHF. In quiescent myocyte preparations, control myocytes secreted ET (2.29 +/- 0.45 amol.cell-1.h-1), which was similar in CHF myocytes. These findings suggest that the production of ET may have important and potentially differential effects on contractile function with the development of CHF.

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

“…Nuclear localization of ECE-1a and ECE-1b has already been demonstrated in human microvascular endothelial cells, human umbilical vein endothelial cells, and transfected CHO cells [69,70]. Moreover, ET-1 is produced, stored and secreted by neonatal [71] and adult cardiac ventricular myocytes [72] under basal conditions, and regulated in response to stretch [73], electrical stimulation [72], or extracellular ET-1 (Supplemental Figure 2). Interestingly, although the basal level of ET-1 production in ventricular myocytes from failing hearts is unchanged, the effect of electrical stimulation on ET-1 secretion is reduced [72].…”

“…Moreover, ET-1 is produced, stored and secreted by neonatal [71] and adult cardiac ventricular myocytes [72] under basal conditions, and regulated in response to stretch [73], electrical stimulation [72], or extracellular ET-1 (Supplemental Figure 2). Interestingly, although the basal level of ET-1 production in ventricular myocytes from failing hearts is unchanged, the effect of electrical stimulation on ET-1 secretion is reduced [72]. In endothelial cells, ET-1 production is regulated at the level of transcription, mRNA stability, and maturation of the ET precursor protein, preproendothelin.…”

Endothelin receptor blockade has an oxygen-saving effect in Dahl salt-sensitive rats with heart failure

“…In contrast, data from other models suggest that ET-1 may have a blunted positive or even a negative inotropic effect (14,32,33,36). These inconsistencies may result from effects of antagonist-induced changes in loading conditions (decreased vascular resistance) on conventional measures of LV performance as well as variable anesthesia, species, HF severity, and experimental preparation.…”

Protein Kinase C Isoform Activation and Endothelin-1 Mediated Defects in Myocyte Contractility After Cardioplegic Arrest and Reperfusion

“…[2][3][4] Moreover, elevated ET-1 levels in patients during and after cardiac surgery requiring CA may contribute to a complex postoperative course. 3 Although the effects of ET-1 on LV pump function after CA are likely to be multifactorial, ET-1 has been demonstrated to modulate myocyte contractile function, [5][6][7] which in turn can influence LV function. Accordingly, the overall goal of this study was to identify specific components of ET-1-mediated signaling using an isolated myocyte model of simulated CA.…”