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
[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).


RESULTS
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.


CONCLUSIONS
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.
Backs
Johannes
J
Department of Cardiology, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany. johannes.backs@web.de
Bresch
Elke
E
Lutz
Matthias
M
Kristen
Arnt V
AV
Haass
Markus
M
D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008454:Mazindol / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D010477:Perfusion; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D002352:Carrier Proteins; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; C107831:darusentan; D008454:Mazindol; D009638:Norepinephrine