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

• Published in: Cardiovascular research 2005-08, Vol.67 (2), p.283-290
• Main Authors: BACKS, Johannes, BRESCH, Elke, LUTZ, Matthias, KRISTEN, Arnt V, HAASS, Markus
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biological Transport; Cardiology. Vascular system; Carrier Proteins - metabolism; Endothelin-1 - antagonists & inhibitors; Endothelin-1 - metabolism; Endothelin-1 - pharmacology; Heart; Heart Failure - metabolism; Heart Failure - physiopathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Male; Mazindol - metabolism; Medical sciences; Myocardial Contraction; Myocardium - metabolism; Neurons - metabolism; Norepinephrine - metabolism; Perfusion; Phenylpropionates - pharmacology; Pyrimidines - pharmacology; Rats; Rats, Wistar
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/j.cardiores.2005.03.018

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. [3H]-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 [3H]-mazindol binding. Experimental heart failure in rats was induced by transverse aortic constriction (TAC). ET-1 inhibited cardiac [3H]-NE-uptake in a concentration- and time-dependent manner. The endothelin A receptor (ET(A)) antagonist BQ123 but not the endothelin B receptor (ET(B)) antagonist BQ788 abolished ET-1-induced reduction of [3H]-NE-uptake. Likewise, ET-1, but not the ET(B) 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 ET(B). In isovolumically contracting healthy hearts, ET-1 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, ET(A) antagonism by darusentan improved both impairment of cardiac [3H]-NE-uptake and reduction of [3H]-mazindol binding sites. ET-1 inhibits cardiac NE re-uptake via ET(A) but attenuates exocytotic NE release via ET(B), resulting in opposite effects on cardiac NE net release. In healthy hearts, ET(A)-mediated inhibition of NE re-uptake exceeds ET(B)-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.