Zusammenfassung
The beta-adrenergic receptor system not only plays a central role
in modulating heart rate and left-ventricular (LV) contractility,
but is also involved in the development of heart failure. We have,
recently, shown that heart-specific overexpression of the beta(1)-adrenergic
receptor in transgenic mice (TG) initially leads to increased contractility,
followed by LV hypertrophy and heart failure. Since one feature for
all forms of heart failure are characteristic changes in myocardial
energy metabolism, we asked whether alterations in energetics are
detectable in these mice before signs of LV impairment are present.
Myocardial energetics ((31)P NMR spectroscopy) and LV performance
were measured simultaneously in isolated perfused hearts at different
workloads. LV performance as well as contractile reserve was identical
for hearts of 4-month-old TG and wild-type mice. The ratio of phosphocreatine
to ATP (1.16 +/- 0.05 vs. 1.46 +/- 0.10) and total creatine content
(17.6 +/- 1.2 vs. 22.6 +/- 0.9 mmol/l) were significantly reduced
in TG. Furthermore, there was a significant decrease in creatine
transporter content (-43%), mitochondrial (-44%) and total creatine
kinase (CK) activity (-21%) as well as citrate synthase activity
(-25%), indicating impaired oxidative energy generation in TG. In
conclusion, these findings of alterations in the CK system, creatine
metabolism and mitochondrial proteins in TG hearts prior to the development
of LV dysfunction provide further evidence that changes in myocardial
energetics play a central role in the deterioration of cardiac function
after chronic beta-adrenergic stimulation.
Nutzer