Effects of a DA2/alpha2 agonist and a beta1-blocker in combination with an ACE inhibitor on adrenergic activity and left ventricular remodeling in 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. 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.
Masson
S
S
Department of Cardiovascular Research, Instituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Masseroli
M
M
Fiordaliso
F
F
Calvillo
L
L
D'Aquila
S
S
Bernasconi
R
R
Garrido
G
G
Torri
M
M
Razzetti
R
R
Bongrani
S
S
Latini
R
R
D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003327:Coronary Disease / Q000150:complications*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D009638:Norepinephrine / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D018491:Dopamine Agonists; D018377:Neurotransmitter Agents; D018342:Receptors, Adrenergic, beta-1; D017448:Receptors, Dopamine D2; D009638:Norepinephrine