Norepinephrine-induced acute heart failure in transgenic mice overexpressing erythropoietin.
OBJECTIVE
Overexpression of erythropoietin (Epo) in mice (Epo-tg6) leads to an increase in hematocrit and blood volume, and strongly reduces endurance upon exercise. It was the aim of this study to characterize the mechanisms underlying the reduced cardiac performance.


METHODS
Left (LV) and right (RV) ventricular function was measured with and without norepinephrine (NE) stimulation in 12 anaesthetized Epo-tg6 and in 13 wild-type (WT) control mice.


RESULTS
There were no differences in heart function under baseline resting conditions. Stimulation with NE (10 microl bolus injections of 1-100 ng per mouse) in WT mice led to a dose-dependent increase in heart rate (HR), LV developed pressure (LVDP) and rate of rise in LV pressure (LV dP/dt(max)), while LV end-diastolic pressure (LVEDP) was unchanged. Except for HR, these parameters increased to a lesser extent in EPO-tg6 mice. Strikingly, LVEDP strongly increased in Epo-tg6 mice after NE (up to >20 mmHg). Eleven out of 13 Epo-tg6, but none of the WT mice died or required resuscitation after high-doses of NE. In these cases severe diastolic dysfunction became overt since the relative myocardial relaxation time was significantly prolonged and the duration of diastole was shortened. Moreover, the ECG showed a marked ST segment depression as well as deep negative T-waves. The NE-induced reduction in myocardial adenosin-triphosphate (ATP) content was more pronounced in Epo-tg6 mice after 10 min of continuous NE infusion (50 ng/min per mouse).


CONCLUSIONS
NE-induced stress in Epo-tg6 mice led to acute heart failure associated with diastolic dysfunction and myocardial ischemia.
Deten
Alexander
A
Carl-Ludwig-Institute of Physiology, Leipzig University, Liebigstrasse 27, D-04103 Leipzig, Germany. deta@medizin.uni-leipzig.de
Shibata
Junpei
J
Scholz
Dimitri
D
Briest
Wilfried
W
Wagner
Klaus F
KF
Wenger
Roland H
RH
Zimmer
Heinz-Gerd
HG
D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D003971:Diastole; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004921:Erythropoietin / Q000235:genetics* / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D009638:Norepinephrine / Q000494:pharmacology*; D013268:Stimulation, Chemical; D017725:Ventricular Pressure / Q000187:drug effects
D004921:Erythropoietin; D000255:Adenosine Triphosphate; D009638:Norepinephrine