Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension

Abstract

Right heart failure is the major cause of death in Pulmonary Artery Hypertension (PAH) patients but is not a current, specific therapeutic target. Pre-clinical studies have shown that adrenoceptor blockade can improve cardiac function but the mechanisms of action within right ventricular (RV) myocytes are unknown. We tested whether the β1–adrenoceptor blocker metoprolol could improve RV myocyte function in an animal model of PAH, by attenuating adverse excitation-contraction coupling remodeling. PAH with RV failure was induced in rats by monocrotaline injection. When PAH was established, animals were given 10 mg/kg/day metoprolol (MCT + BB) or vehicle (MCT). The median time to the onset of heart failure signs was delayed from 23 days (MCT), to 31 days (MCT + BB). At 23 ± 1 days post-injection, MCT + BB showed improved in vivo cardiac function, measured by echocardiography. RV hypertrophy was reduced despite persistent elevated afterload. RV myocyte contractility during field stimulation was improved at higher pacing frequencies in MCT + BB. Preserved t-tubule structure, more uniform evoked Ca2+ release, increased SERCA2a expression and faster ventricular repolarization (measured in vivo by telemetry) may account for the improved contractile function. Sarcoplasmic reticulum Ca2+ overload was prevented in MCT + BB myocytes resulting in fewer spontaneous Ca2+ waves, with a lower pro-arrhythmic potential. Our novel finding of attenuation of defects in excitation contraction coupling by β1–adrenoceptor blockade with delays in the onset of HF, identifies the RV as a promising therapeutic target in PAH. Moreover, our data suggest existing therapies for left ventricular failure may also be beneficial in PAH induced RV failure.

Mitochondrial function remains impaired in the hypertrophied right ventricle of pulmonary hypertensive rats following short duration metoprolol treatment

“…Despite this, observational trials of PH patients who receive β-AR blockers for co-morbidity reasons demonstrated the safety of the drugs in this cohort [16, 17]. Promising preclinical experimental evidence for β-AR blocker treatment for right heart failure in rat models of PH is now emerging [18–22].…”

Metoprolol alleviates arginine vasopressin-induced cardiomyocyte hypertrophy by upregulating the AKT1–SERCA2 cascade in H9C2 cells

“…Metoprolol is a selective β1-adrenoceptor inhibitor, that has been widely used to improve heart function [36,37]. Many studies have shown that long-term treatment with Met could downregulate collagen I and III mRNA levels, and modulate stem cell characteristics to prevent progressive pathological remodeling, in addition, Met could improve the Ca 2+ handling and contractility of right ventricular (RV) myocytes isolated from monocrotaline (MCT)-treated rats [18,[38][39][40]. In embryonic development, β-adrenoceptor stimulation leads to decreased AKT phosphorylation [41].…”

“…Metoprolol (Met) is a β-blocker widely used to inhibit cardiac hypertrophy and to improve cardiac function [18,19]. Nebivolol, which is a third-generation β-blocker, has antihypertrophic effects in models of neonatal cardiomyocyte hypertrophy [20].…”

The Protective Effect of Qishen Granule on Heart Failure after Myocardial Infarction through Regulation of Calcium Homeostasis

“…Calcium influx is also considered to account for many detrimental effects of traditional inotropic drugs, such as glycosides digoxin [ 26 ]. Imbalance of calcium homeostasis in the cardiomyocytes not only directly interferes myocardial contraction and relaxation through calcium/calmodulin-dependent proteins but also exacerbates the heart failure process by interacting with other pathophysiological factors such as the β -adrenergic signaling pathway and renin-angiotensin-aldosterone system (RAAS) [ 27 – 30 ]. These pathophysiological changes were also confirmed by our experimental results.…”