Carvedilol Prevents Ovariectomy-Induced Myocardial Contractile Dysfunction in Female Rat

Abstract

Carvedilol has beneficial effects on cardiac function in patients with heart failure but its effect on ovariectomy-induced myocardial contractile dysfunction remains unclear. Estrogen deficiency induces myocardial contractile dysfunction and increases cardiovascular disease risk in postmenopausal women. Our aim was to investigate whether carvedilol, a beta receptor blocker, would prevent ovariectomy-induced myocardial contractile dysfunction. Female rats (8 weeks old) that underwent bilateral ovariectomy were randomly assigned to receive daily treatment with carvedilol (OVX+CAR, 20 mg/kg), placebo (OVX) and SHAM for 58 days. Left ventricle papillary muscle was mounted for isometric tension recordings. The inotropic response to Ca2+ (0.62 to 3.75 mM) and isoproterenol (Iso 10−8 to 10−2 M) were assessed. Expression of calcium handling proteins was measured by western blot analysis. Carvedilol treatment in the OVX animals: prevented weight gain and slight hypertrophy, restored the reduced positive inotropic responses to Ca2+ and isoproterenol, prevented the reduction in SERCA2a expression, abolished the increase in superoxide anion production, normalized the increase in p22phox expression, and decreased serum angiotensin converting enzyme (ACE) activity. This study demonstrated that myocardial contractile dysfunction and SERCA2a down regulation were prevented by carvedilol treatment. Superoxide anion production and NADPH oxidase seem to be involved in this response.

Antenatal Hypoxia Induces Programming of Reduced Arterial Blood Pressure Response in Female Rat Offspring: Role of Ovarian Function

“…However, 3 months after OVX treatment, the OVX rats had significantly higher body weights than the sham groups, suggesting that ovaries play an important role in regulation of female body weight. Similar findings have been reported in previous studies [34] , [35] . EI-Seweidy et al [34] have also demonstrated that OVX-mediated increased body weights can be reversed by 6 weeks estrogen replacement treatment.…”

Obese-insulin resistance accelerates and aggravates cardiometabolic disorders and cardiac mitochondrial dysfunction in estrogen-deprived female rats

“…It has been shown that a cardiac sympathovagal imbalance is commonly found in postmenopausal women, and estrogen replacement helps improve this cardiac autonomic dysfunction (Yang et al 2013). Estrogen deficiency has been shown to reduce myocardium contractile response to calcium and betaadrenergic receptor stimulation indicating contractile dysfunction of the heart (Ribeiro et al 2013). Depletion of endogenous estrogen also causes endothelial dysfunction indicated by decreased endothelial relaxation and increased endothelial contraction of arterioles via reactive oxidative species augmentation and vascular nitric oxide reduction (Wang et al 2014).…”

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

“…However, in other studies, no change was observed in the expression of NCX expression in both oestrogen treatment and OVX animals . Although oestrogen decreased the expression of PLB, and OVX increased its expression, no change in expression was found in other reports . On the other hand, oestrogen downregulated the RyR expression, while in other reports both OVX and oestrogen treatments had no effect on RyR expression .…”

“…Therefore, the efficacy of β‐blockers and Ca 2+ blockers may vary with gender or age groups based on the interplay between ERs and βARs. As demonstrated, carvedilol, a non‐selective β‐blocker, protected against myocardial contractile dysfunction caused by oestrogen deficiency . Interestingly, this is one of the β‐blockers to display biased agonism and it too can activate the β 2 AR‐G αi /β‐arrestin pathways .…”