Effects of a DA(2)/alpha(2) agonist and a beta(1)-blocker in combination with an ACE inhibitor on adrenergic activity and left ventricular remodelingin an experimental model of left ventricular dysfunction after coronary artery occlusion

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. Becau se 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 (de lapril) with a DA(2)-dopaminergic receptor/alpha(2)-adrenoceptor agonist (C HF-1024) or a beta 1-adrenoceptor antagonist (metoprolol) after a moderate to large myocardial infarction (MI) in rats. MI was induced by left coronar y 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 CH F-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 circulat ing concentration were measured. Hemodynamic variables were measured, and t hree-dimensional morphometric analysis was done on the diastole- arrested h earts to quantify infarct size and LV geometry. In conscious animals, delap ril alone or with CHF-1024 or metropolol did not modify heart rate or systo lic blood pressure. Both combination treatments, however, significantly red uced heart rate in anesthetized animals compared with the group receiving v ehicle. Infarct size was not different between treatments, averaging 20-22% of LV volume. The threefold increase of LV chamber volume in infarcted rat s was significantly attenuated by delapril alone or with CHF-1024 or metopr olol (-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 excreti on 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 delap ril having no hemodynamic effect, reduced LV volume in a model of chronic h eart failure. When CHF-1024 or metoprolol was given with delapril, sympathe tic activation decreased with no unwanted effects, such as excessive hypote nsion.