Reversal of Cardiac Remodeling and Subcellular Defects by Prazosin in Heart Failure Due to Myocardial Infarction

Abstract

Background: This study was undertaken to test if α-Adrenoceptor (AR) blockade with prazosin reverses cardiac remodeling and ameliorates subcellular defects in heart failure due to Myocardial Infarction (MI).Methods: Heart failure in rats was induced by MI for 12 wks and then treated with or without prazosin (10 mg/kg/ day) for 8 wks. Both control and experimental animals were assessed hemodynamically and echocardiographically for evaluating changes in heart function and cardiac remodeling, respectively. Left Ventricle (LV) was used for determining biomedical and molecular activities.Results: Cardiac dysfunction, as evident from depressed LV systolic pressure, rates of changes in pressure development and decay, cardiac output, ejection fraction and fractional shortening as well as increased LV end diastolic pressure, in 20 wks infarcted animals, was corrected partially by prazosin treatment. Different parameters of cardiac remodeling including increased LV posterior wall thickness and LV systolic diameter in failing hearts were fully or partially reversed whereas increased LV diastolic diameter was unaltered by prazosin therapy. Reversal of lung congestion and cardiac hypertrophy in MI animals by prazosin was associated with depression in the elevated levels of plasma norepinephrine, unlike epinephrine or dopamine. Depressions in Sarcoplasmic Reticular (SR) Ca 2+ -uptake activity as well as protein content for Ca 2+ -pump ATPase and phospholamban in failing hearts were reversed partially whereas depressed SR Ca 2+ -release activity and myofibrillar Ca 2+ -stimulated ATPase activity were not affected by prazosin. Alterations in mRNA levels for SR Ca 2+ -pump ATPase, SR Ca 2+ -release channels, and α-myosin heavy chain and β-myosin heavy chain in MI-induced heart failure were not influenced by prazosin treatment. Conclusions:It is suggested that the activation of α-AR system may be associated with cardiac remodeling and heart failure and the reverse cardiac remodeling by α-AR blockade may improve cardiac performance by attenuating defects in SR Ca 2+ -pump.

Reversal of cardiac dysfunction and subcellular alterations by metoprolol in heart failure due to myocardial infarction

“…Such alterations in cardiac performance in 20 weeks MI animals may be due to the development of cardiac remodeling, which was evident from increased LVIDd, LVIDs, LVPWs, and LVPWd as well as decreased IVSs without any changes in IVSd. This view is in agreement with previous reports indicating cardiac remodeling in rats due to MI for a period of 8–20 weeks (Sanganalmath et al, ; Machackova et al, ; Dhalla et al, ; Babick et al, ). The observed cardiac remodeling in response to a loss of myocardium in the 20 weeks MI animals with heart failure may not be due to increased pressure or work load on the heart because both MAP and HR as well as the infarct size were not altered.…”

“…This view is supported by our observations that both protein content and mRNA levels for SR Ca 2+ ‐pump and PLB were depressed whereas gene expression for α‐MHC was decreased and that for β‐MHC was increased in the 20 weeks infarcted hearts. Varying degrees of defects in SR and MF activities, protein content and gene expression have also been reported in 8–20 weeks MI animals (Wang et al, ; Guo et al, ; Shao et al, ; Dhalla et al, ; Babick et al, ). These subcellular defects in the failing heart are most likely to be due to activation of both SNS and RAS (Dhalla et al, ).…”

“…Although NE release from sympathetic nerve is considered to be dependent upon the stimulation of β 2 ‐ARs and α 2 ‐ARs present on the sympathetic nerve endings, it should be noted that β‐AR antagonists have been reported to depress NE release due to their actions on the preterminal nerve endings (Majewski et al, 1980). Blockade of α‐ARs by prazosin has also been found to decrease the elevated level of plasma NE, unlike the elevated levels of dopamine, in MI animals (Babick et al, ). In view of our finding that treatment of MI animals with losartan, an angiotensin receptor (AT 1 R) antagonist, augmented the increased level of NE but depressed the increased level of dopamine (Babick et al, ), it is evident that NE release from the sympathetic nerve endings in the MI hearts is modulated by AT 1 Rs.…”

“…This may be due to the use of low doses of metoprolol and thus further experiments with high doses of metoprolol in this model of heart failure are required to distinguish between rate‐dependent and rate‐independent effects of metoprolol treatment. Nonetheless, it is pointed out that improvement in cardiac function without any changes in HR in 20 weeks MI‐induced heart failure has also been observed upon treatments with other interventions such as prazosin and losartan (Babick et al, ). Furthermore, treatment of 8 weeks MI‐induced heart failure with both low and high doses of propranol and atenolol were found to improve heart function and decrease HR (Machackova et al, ).…”

The role of the sympathetic nervous system in sudden cardiac death

“…Normal stimulation of α-adrenoceptors has a positive chronotropic effect; however, prolonged stimulation has been implicated in myocyte hypertrophy, myocardial ischemia, metabolic derangements and eventual cardiomyocyte apoptosis and the development of dilated cardiomyopathy (40)(41)(42). Despite this possible negative effect, neither the α-adrenoceptor density nor the positive inotropic effect of norepinephrine is distorted in failing human hearts, leading to the consideration that the α-adrenoceptor stimulation may be an adaptive mechanism in failing hearts (43). It should also be mentioned that stimulation of ß-adrenergic receptors by catecholamines activates adenylyl cyclase, causing the conversion of ATP to cAMP, a process that depletes high-energy phosphate stores (1,44).…”