Influence of Prenatal Alcohol Exposure on Myocardial Contractile Function in Adult Rat Hearts: Role of Intracellular Calcium and Apoptosis

Abstract

To assess the teratogenic action of ethanol on cardiac contractile function in offspring exposed to ethanol in utero, pregnant Sprague-Dawley rats were fed with ethanol during gestation. Left-ventricular papillary muscles and myocytes were isolated from the offspring of the ethanol-ingesting and control pregnant rats. Mechanical parameters measured were peak tension development (PTD, indicating the myocardial force-generating capacity), peak cell shortening (PS), time-to-PTD/PS (TPT/TPS), time-to-90% relaxation/re-lengthening (RT(90)/TR(90)), and maximal velocities of contraction/shortening and relaxation/re-lengthening (+/- VT and +/- dL/dt). Intracellular Ca(2+) levels and apoptosis were evaluated with fura-2 fluorescent dye and Caspase-3 activation assay, respectively. Offspring of the ethanol group displayed decreased heart weight associated with comparable body, liver and kidney weight, and papillary muscle weight/size, compared to the control group. However, prenatal ethanol exposure depressed myocardial PTD and +/- VT. The myocardium from the ethanol group also exhibited slightly but significantly shortened TPT, accompanied with normal RT(90). Muscles from both groups exhibited comparable responses to post-rest potentiation, increasing extracellular Ca(2+) concentration, noradrenaline and acute ethanol challenge. Ventricular myocytes from both the control and ethanol groups possessed similar PS, TPS, TR(90) and +/- dL/dt. Both resting and peak intracellular Ca(2+) levels were elevated in myocytes from the ethanol group. Additionally, acute ethanol application depressed caffeine-induced intracellular Ca(2+) rise in myocytes from both groups. Myocytes from the ethanol group displayed an enhanced Caspase-3 activation, compared to control myocytes. These results suggest that prenatal ethanol exposure alters myocardial contractile function and may contribute to the development of postnatal cardiac dysfunction through, in part, increased intracellular Ca(2+) loading and apoptosis.

Alcohol exposure during late gestation adversely affects myocardial development with implications for postnatal cardiac function

“…A number of in vivo and in vitro studies have reported induction of apoptosis in cardiomyocytes in the presence of EtOH (7,30). In support of these findings, we found marked increases in the relative mRNA levels of the proapoptotic genes caspase 3 (P ϭ 0.007) and BAX (P ϭ 0.057) in the myocardium of EtOH-exposed fetuses, but there were no differences in the proliferative gene c-Myc.…”

“…Previous studies have reported that exposure to EtOH induces apoptosis of cardiomyocytes both in vivo and in vitro (7,30); in addition, reductions in the in vivo circulating concentrations of the cardiomyocyte growth factor, insulin-like growth factor (IGF)-1, have been reported following EtOH exposure (14). We therefore hypothesized that fetal exposure to EtOH during late gestation would adversely impact on the growth and maturation of cardiomyocytes, as a result of an increase in apoptotic activity and a decrease in IGF expression, leading to a reduction in the complement of cardiomyocytes at birth; we also expected increased extracellular matrix deposition in the myocardium because EtOH increases fibrosis in the adult heart (29,34).…”

Sexually dimorphic effects of maternal alcohol intake and adrenalectomy on left ventricular hypertrophy in rat offspring

“…Prenatal ethanol exposure has been shown to cause ultrastructural abnormalities in cardiac muscle cells in mice (63) and a significant difference in left ventricular muscle width in male rats (41). The high incidence of heart defects indicates that alcoholism during pregnancy has to be considered as a serious and preventable cause of congenital heart disease.…”

A study of the consequences of early gestational ethanol and/or nicotine exposure in the mouse

“…In addition to these, the usage of animal models has allowed for the investigation of a wide range of other phenotypes resultant of prenatal ethanol exposure: impairments to behaviour (Sanchez Vega et al, 2013), glucose metabolism (Harper et al, 2014), adiposity (Dobson et al, 2012), renal (Gray et al, 2010) and cardiovascular (Ren et al, 2002) function, lung development (Probyn et al, 2013), hypothalamic-pituitary-adrenal function (Lan et al, 2009), and even osteoarthritis risk (Ni et al, 2015).…”

“…These phenotypes include abnormal neural development and behaviour (Sanchez Vega et al, 2013;Zhang et al, 2015), growth retardation (Kaminen-Ahola et al, 2010b;Probyn et al, 2012;Gardebjer et al, 2014) and craniofacial abnormalities (Sulik et al, 1981;Anthony et al, 2010;Kaminen-Ahola et al, 2010b), metabolic perturbations (Dobson et al, 2012;Harper et al, 2014), as well as the abnormal development and function of the renal, cardiovascular and pulmonary systems (Ren et al, 2002;Gray et al, 2010;Probyn et al, 2013).…”