Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function

Endothelin-1 (ET-1) has acute positive inotropic effects, but consequences of chronically increased ET-1 on contractile function of cardiac myocytes are largely unknown. In the present study, effects of long-term treatment with ET-1 ( 10 nM) for 5 days on both force development [ force of contraction (FOC)] and kinetics of contraction were determined in heart tissue reconstituted from rat cardiac cells. Isometric force was measured in response to cumulative concentrations of Ca2+ and isoprenaline. ET-1 augmented basal FOC by 64 +/- 11% ( P < 0.05), which was associated with a significantly blunted contractile response to Ca2+ and isoprenaline. Moreover, ET-1 significantly prolonged relaxation ( 62 +/- 3 vs. 53 +/- 2 ms). Selective ETA (BQ- 123) and ETB receptor blockade ( BQ- 788) demonstrated that effects of ET-1 on contractile function were mediated through the ETA receptor subtype. Effects of ET-1 were prevented by cotreatment with either Ro31-8425, a PKC inhibitor, or dimethylamiloride, an inhibitor of the Na+/H+ exchanger. In contrast to long-term ET-1 treatment, no changes in contractile parameters were observed after ET-1 treatment for 3 h before force measurement. These data suggest that chronic ET-1 stimulation has dual effects on contractility: improvement of basal force but impairment of twitch kinetics and inotropic responsiveness to β-adrenoceptor stimulation. The signaling pathways involved include ETA receptors, PKC, and the Na+/H+ exchanger. The present in vitro findings raise the possibility that ET-1 may exert both adaptive and maladaptive effects in the failing myocardium in which local accumulation of ET-1 is present.