Comparative efficacy of a DA2/alpha2 agonist and a beta-blocker in reducing adrenergic drive and cardiac fibrosis in an experimental model of left ventricular dysfunction after coronary artery occlusion.
Attenuation of neuroendocrine activation may be beneficial in congestive heart failure. Sympathetic nervous system overactivity can be reduced by receptors blockade or by reducing norepinephrine (NE) spillover. This study evaluated and compared the effects of a DA2-dopaminergic receptor/alpha2-adrenoceptor agonist (CHF-1024) and a beta1-adrenoreceptor antagonist in terms of hemodynamics, ventricular remodeling, beta-adrenergic drive, and cardiac fibrosis after myocardial infarction (MI) in rats. MI was induced by left coronary artery ligation in 213 rats, whereas 12 were left unoperated on. After 2 months, the operated-on animals were treated for 1 more month with CHF-1024 at either 0.33 mg/kg/day (low dose) or 1 mg/kg/day (high dose) or with metoprolol (10 mg/kg/day), delivered through implanted osmotic minipumps. Plasma concentration and urinary excretion of NE were measured before the rats were killed. Hemodynamic variables were measured and morphometric analysis was done on the diastole-arrested hearts to quantify left ventricular remodeling and interstitial collagen density. Metoprolol treatment tended to normalize LV end-diastolic pressure (LVEDP). CHF-1024 at either dose, and metoprolol, significantly reduced collagen deposition in LV of infarcted animals (from 8.8 +/- 0.5% LV area in vehicle-treated rats to 6.6 +/- 0.2% or 6.4 +/- 0.2% after the low or high dose of CHF-1024, respectively; p < 0.05). Similarly, CHF-1024 at either dose reduced the plasma concentration of NE (from 224 +/- 53 pg/ml to 60 +/- 7 pg/ml or 87 +/- 13 pg/ml; p < 0.05) and urinary excretion of NE in rats with MI, whereas beta-blockade did not affect these variables. In conclusion, CHF-1024 infused for 1 month to rats with LV dysfunction reduced heart rate, NE spillover, and collagen deposition, without unwanted effects, only appearing at the higher dose. Effective beta-blockade with metoprotol reduced LVEDP with no effects on heart function. Neither DA2/alpha2 stimulation nor beta-blockade altered LV remodeling after coronary artery ligation.
Latini
R
R
Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche, Mario Negri, Milan, Italy.
Masson
S
S
Jeremic
G
G
Luvarà
G
G
Fiordaliso
F
F
Calvillo
L
L
Bernasconi
R
R
Torri
M
M
Rondelli
I
I
Razzetti
R
R
Bongrani
S
S
D058647:Adrenergic alpha-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000652:urine; D003094:Collagen / Q000378:metabolism; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000188:drug therapy*; D009206:Myocardium / Q000473:pathology; D009638:Norepinephrine / Q000097:blood / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000503:physiopathology
D058647:Adrenergic alpha-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D017448:Receptors, Dopamine D2; D013764:Tetrahydronaphthalenes; D003094:Collagen; D008790:Metoprolol; C112301:CHF 1024; D009638:Norepinephrine