Carvedilol Prevents Ovariectomy-Induced Myocardial Contractile Dysfunction in Female Rat

Rogerio Faustino Ribeiro,Brunella M M Pavan,Felipe F Potratz,Ivanita Stefanon,Ludimila Forechi,Aurelia Araujo Fernandes,Jonaina Fiorim,Filipe Lugon Moulin Lima,Dalton Valentim Vassallo,Rudolf Kirchmair

doi:10.1371/journal.pone.0053226

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.

Highlights

Cardiovascular diseases are the leading cause of death in developed countries and are more prevalent in men as compared to premenopausal women [1,2,3,4]
We demonstrated that myocardial contractile dysfunction induced by ovariectomy and expression of key Ca2+-handling proteins were prevented by losartan treatment and that AT1 receptor activation is involved in this response [16]
We found a difference in the inotropic response to calcium between the OVX and SHAM groups for all concentrations studied (Figure 1A); the OVX group response is approximately 50% less compared to the SHAM rats

Summary

Introduction

Cardiovascular diseases are the leading cause of death in developed countries and are more prevalent in men as compared to premenopausal women [1,2,3,4]. Despite aggressive diagnosis and treatment, cardiovascular diseases still remain a major and growing public health problem [5]. It is well known that estrogen is linked to cardiovascular protection in premenopausal women whereas hormone replacement therapy (HRT) may have detrimental effects on cardiovascular function [6,7,8]. Estrogen deficiency plays a role in the contractile activity of the heart [11,12,13] most likely by decreasing SERCA2a expression and its function, decreasing Ca2+ responsiveness of myofilament activation and increasing phospholamban expression [1,9,14]. We demonstrated that myocardial contractile dysfunction induced by ovariectomy and expression of key Ca2+-handling proteins were prevented by losartan treatment and that AT1 receptor activation is involved in this response [16]

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