Endothelin-1 inhibits the neuronal norepinephrine transporter in hearts of male rats

Objective: Endothelin-1 (ET-1) potentiates norepinephrine (NE)-induced contractile responses. An impairment of cardiac NE re-uptake by the neuronal NE transporter (NET) contributes to an increased NE net release in failing hearts. We hypothesized that both phenomena are caused by ET-1-mediated inhibition of NET. Methods: [H-3]-NE-uptake, electrical field stimulation-evoked NE overflow and left ventricular contractility (LV-dp/dt(max)) were measured in isolated perfused rat hearts. NET density on cardiac plasma membranes was determined by [H-3]-mazindol binding. Experimental heart failure in rats was induced by transverse aortic constriction (TAC). Results: ET-1 inhibited cardiac [H-3]-NE-uptake in a concentration- and time-dependent manner. The endothelin A receptor (ETA) antagonist BQ123 but not the endothelin B receptor (ETB) antagonist BQ788 abolished ET-1-induced reduction of [H-3]-NE-uptake. Likewise, ET-1, but not the ETB agonist sarafotoxin S6c, enhanced the stimulated overflow of endogenous NE. In contrast, ET-I inhibited the stimulated NE overflow during NET blockade (exocytotic NE release) via activation of ETB. In isovolumically contracting healthy hearts, ET-I potentiated the NE- but not isoprenaline-induced increase in LV-dp/dt(max). Since isoprenaline is not a NET substrate, the enhanced LV-dp/dt(max) response to NE thus depends on NET. In TAC rats, ETA antagonism by darUsentan improved both impairment of cardiac [H-3]-NE-uptake and reduction of [H-3]-mazindol binding sites. Conclusion: ET-I inhibits cardiac NE re-uptake via ETA but attenuates exocytotic NE release via ETB, resulting in opposite effects on cardiac NE net release. In healthy hearts, ETA-mediated inhibition of NE re-uptake exceeds ETB-mediated silencing of NE release and potentiates the NE-induced increase in left ventricular contractility. In TAC rats, endogenous ET-I impairs NE re-uptake and promotes sympathetic overstimulation of failing hearts. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.