Comparative Efficacy of a DA2/α2 Agonist and a β-Blocker in Reducing Adrenergic Drive and Cardiac Fibrosis in an Experimental Model of Left Ventricular Dysfunction After Coronary Artery Occlusion

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Abstract

Summary:

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/α2-adrenoceptor agonist (CHF-1024) and a β1-adrenoreceptor antagonist in terms of hemodynamics, ventricular remodeling, β-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 β-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 β-blockade with metoprotol reduced LVEDP with no effects on heart function. Neither DA2/α2 stimulation nor β-blockade altered LV remodeling after coronary artery ligation.

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