Copyright © 2005, European Society of Cardiology
Endothelin-1 inhibits the neuronal norepinephrine transporter in hearts of male rats
Department of Cardiology, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany
* Corresponding author. Tel.: +49 6221 568611; fax: +49 6221 565515. Email address: johannes.backs{at}web.de
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: [3H]-NE-uptake, electrical field stimulation-evoked NE overflow and left ventricular contractility (LV-dp/dtmax) were measured in isolated perfused rat hearts. NET density on cardiac plasma membranes was determined by [3H]-mazindol binding. Experimental heart failure in rats was induced by transverse aortic constriction (TAC).
Results: ET-1 inhibited cardiac [3H]-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 [3H]-NE-uptake. Likewise, ET-1, but not the ETB agonist sarafotoxin S6c, enhanced the stimulated overflow of endogenous NE. In contrast, ET-1 inhibited the stimulated NE overflow during NET blockade (exocytotic NE release) via activation of ETB. In isovolumically contracting healthy hearts, ET-1 potentiated the NE- but not isoprenaline-induced increase in LV-dp/dtmax. Since isoprenaline is not a NET substrate, the enhanced LV-dp/dtmax response to NE thus depends on NET. In TAC rats, ETA antagonism by darusentan improved both impairment of cardiac [3H]-NE-uptake and reduction of [3H]-mazindol binding sites.
Conclusion: ET-1 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-1 impairs NE re-uptake and promotes sympathetic overstimulation of failing hearts.
KEYWORDS Autonomic nervous system; Norepinephrine; Norepinephrine transporter; Endothelins; Heart failure
1 Current address: UT Southwestern, 5323 Harry Hines Blvd., Dallas, TX 75390-9148, USA.
2 Current address: Cardiology and Pneumology, Free University of Berlin, HBD 30, 12200 Berlin, Germany.
3 Current address: Cardiology, Theresienkrankenhaus, Bassermannstrasse 1, 68165 Mannheim, Germany.
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