Renin-
angiotensin-
aldosterone and sympathetic nervous systems overactivity play a major role in worsening the extent of
heart failure. Attenuation of neurohumoral activation with
angiotensin-converting enzyme (
ACE) inhibitors and beta-blockers has proven beneficial in
congestive heart failure. Because ACE inhibition is a recommended treatment for
heart failure, this study was designed to test the effects on neurohumoral activation, hemodynamics, and left ventricular (LV) volume of the combination of an
ACE inhibitor (
delapril) with a DA2-dopaminergic receptor/alpha2-
adrenoceptor agonist (CHF-1024) or a beta1-adrenoceptor antagonist (
metoprolol) after a moderate to large
myocardial infarction (MI) in rats. MI was induced by left coronary artery
ligation in 134 rats, and six were not operated on. After 2 months, the animals with ECG evidence of MI were treated for 1 more month with
CHF- 1024, 0.33 mg/kg/day or with
metoprolol (10 mg/kg/day), delivered through implanted osmotic minipumps, in addition to
delapril (6 mg/kg/day) in the
drinking water. Daily urinary excretion of
norepinephrine (NE) and circulating concentration were measured. Hemodynamic variables were measured, and three-dimensional morphometric analysis was done on the diastole-arrested hearts to quantify
infarct size and LV geometry. In conscious animals,
delapril alone or with
CHF-1024 or metropolol did not modify heart rate or systolic blood pressure. Both combination treatments, however, significantly reduced heart rate in anesthetized animals compared with the group receiving vehicle.
Infarct size was not different between treatments, averaging 20-22% of LV volume. The threefold increase of LV chamber volume in infarcted rats was significantly attenuated by
delapril alone or with
CHF-1024 or
metoprolol (-37 to -44%, p<0.05). Treatment with a combination of the ACEi and
CHF-1024 tended to normalize the shape of the LV cavity. Urinary NE excretion was unaffected by
delapril alone but was reduced by the addition of
CHF-1024 or
metoprolol. In conclusion, 1 month of treatment with doses of
delapril having no hemodynamic effect, reduced LV volume in a model of chronic
heart failure. When
CHF-1024 or
metoprolol was given with
delapril, sympathetic activation decreased with no unwanted effects, such as excessive
hypotension.