Effects of a DA22 agonist and a β1-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

Serge Masson, Marco Masseroli, Fabio Fiordaliso, Laura Calvillo, Silvia D'Aquila, Roberto Bernasconi, Gabino Garrido, Mauro Torri, Roberta Razzetti, Stefano Bongrani, Roberto Latini

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 β-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/α2-adrenoceptor agonist (CHF-1024) or a β1-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.

Original languageEnglish
Pages (from-to)321-326
Number of pages6
JournalJournal of Cardiovascular Pharmacology
Volume34
Issue number3
DOIs
Publication statusPublished - Sep 1999

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Ventricular Remodeling
Coronary Occlusion
Left Ventricular Dysfunction
Angiotensin-Converting Enzyme Inhibitors
Adrenergic Agents
Metoprolol
Coronary Vessels
Theoretical Models
Heart Failure
Hemodynamics
Myocardial Infarction
Adrenergic Receptors
Norepinephrine
Heart Rate
Blood Pressure
Diastole
Sympathetic Nervous System
Angiotensins
Peptidyl-Dipeptidase A
CHF 1024

Keywords

  • Catecholamines
  • CHF- 1024
  • Delapril
  • Heart
  • Left ventricular dysfunction
  • Left ventricular remodeling
  • Metoprolol
  • Myocardial infarction

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Effects of a DA22 agonist and a β1-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. / Masson, Serge; Masseroli, Marco; Fiordaliso, Fabio; Calvillo, Laura; D'Aquila, Silvia; Bernasconi, Roberto; Garrido, Gabino; Torri, Mauro; Razzetti, Roberta; Bongrani, Stefano; Latini, Roberto.

In: Journal of Cardiovascular Pharmacology, Vol. 34, No. 3, 09.1999, p. 321-326.

Research output: Contribution to journalArticle

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KW - Myocardial infarction

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