Effect Of β-Blockers On Cardiac Function And Calcium Handling Protein In Post-infarction Heart Failure Rats

Objective: Heart failure is characterized by progressive myocardial remodeling and deteriorating cardiac function. Intracellular Ca²⁺ homeostasis is critical for efficient myocardial function. Sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) and SERCA regulatory protein phospholamban (PLB) are the major proteins responsible for intracellular Ca²⁺ homeostasis throughout excitation-contraction cycling in cardiomyocytes. Changes in the abundance and/or function of these molecules in heart failure have been variable in previous studies. In the patients with chronic heart failure, treatment with p-adrenergic receptor antagonists led to a reduction in mortality and an improvement of left ventricular function. The major mechanism by which P-adrenergic receptor blockers exert their beneficial effects is blocking the excessively activized sympathetic nervous system. More importantly, it is possible that P-adrenergic receptor blockade indirectly normalizes Ca²⁺-regulatory proteins,resulting in improved intercellular Ca²⁺ cycling and, in turn, reversing cardiac dysfunction. A recent study showed that (β-receptor blocker, propranolol, which can restore the reduction of SERCA in a failing heart. Therefore, we undertook the present study to evaluate the effect of carvedilol on attenuating ventricular remodeling and cardiac contractile dysfunction in rats with heart failure due to acute myocardial infarction (MI) and to compare its effects with those of metoprolol. In order to investigate the molecular mechanism, we also measured and compared the mRNA and protein expression of SERCA, PLB in the failing hearts of rats which were treated with and without different p-blockers.Methods: The proximal left coronary arterial ligation model was employed to induce myocardial infarction (MI) and heart failure in rats. The animals were random assigned to normal control group(n=8), sham-operation group (the surgical process was placed but not ligated, n=8), MI group (n=8), Ml+metoprolol treatment group (60mg/kg/day, n=8), Ml+high dose carvedilol treatment group (30mg/kg/day, n=9)0and MI+low dose carvedilol treatment group (2mg/kg/dag, n=7). Rats were evaluated by echocardiography 2 weeks, 4 weeks and 6 weeks after coronary artery ligation. Six weeks after the initiation of therapy, hemodynamic studies were performed in each group. Then the heart was arrested in diastole and the ventricles were separated and each weighed by an electronic balance. The tissue was cut in asection and stained with hematoxylin and eosin. The myocardial infarct size of each section was calculated. The expression of mRNA and protein of SERCA and PLB in myocytes of non-infarction area were measured using the methods of Reverse Transcription and Polymerase Chain Reaction (RT-PCR) and Western blot.Results: 1. Change of echocardiography: There was a marked increase of left ventricular internal diameter at diastolic phase (LVIDd), left ventricular internal diameter at systolic phase (LVIDs), left ventricular posterior wall thickness at diastolic phase (LVPWd), E waves and E/A in the MI group at 2 weeks after coronary ligation. Left ventricular anterior wall thickness at diastolic phase (LVAWd), LV percent fractional shortening (FS) and A waves were decreased in the MI group at 2 weeks. Thereafter, LVIDd, LVIDs and LVPWd were increased more clearly at 6 weeks. The further decrease of FS was seen at 6 weeks. After 6 weeks of treatment with metoprolol or carvedilol, LVIDs and LVIDd were decreased as compared to the MI group, and FS was increased. LVPWd was also decreased in metoprolol or carvedilol treated groups at 6 weeks, but LVAWd was unchanged. E and A waves and E/A were renewed partly at 4 weeks after β-blocker treatment. Low-dose carvedilol was better in improving FS than metoprolol or high-dose carvedilol.2. Change of hemodynamics: Left ventricular end-diastolic pressure (LVEDP) was increased, systolic blood pressure (SBP), left ventricular systolic pressure (LVSP)and the maximal rate of rise (+dp/dtmax), the maximal rate of fall (-dp/dtmax) were decreas...