Prenatal cocaine exposure increases heart susceptibility to ischaemia–reperfusion injury in adult male but not female rats

Abstract

The present study tested the hypothesis that prenatal cocaine exposure differentially regulates heart susceptibility to ischaemia-reperfusion (I/R) injury in adult offspring male and female rats. Pregnant rats were administered intraperitoneally either saline or cocaine (15 mg kg −1 ) twice daily from day 15 to day 21 of gestational age. There were no differences in maternal weight gain and birth weight between the two groups. Hearts were isolated from 2-month-old male and female offspring and were subjected to I/R (25 min/60 min) in a Langendorff preparation. Preischaemic values of left ventricular (LV) function were the same between the saline control and cocaine-treated hearts for both male and female rats. Prenatal cocaine exposure significantly increased I/R-induced myocardial apoptosis and infarct size, and significantly attenuated the postischaemic recovery of LV function in adult male offspring. In contrast, cocaine did not affect I/R-induced injury and postischaemic recovery of LV function in the female hearts. There was a significant decrease in PKCε and phospho-PKCε levels in LV in the male, but not female, offspring exposed to cocaine before birth. These results suggest that prenatal cocaine exposure causes a sex-specific increase in heart susceptibility to I/R injury in adult male offspring, and the decreased PKCε gene expression in the male heart may play an important role.

Prenatal cocaine exposure abolished ischemic preconditioning-induced protection in adult male rat hearts: role of PKCε

“…Fetal cocaine exposure causes myocardial cell apoptosis, resulting in a decreased number of myocardiocytes at birth and increases the heart's sensitivity to ischemia and reperfusion injury in adult male offspring in a sex-dependent manner (2,4). These studies also showed a correlation between a decrease in both total and phosphorylated protein kinase Cε and increased myocardial sensitivity to ischemia in adult male offspring after fetal cocaine exposure (2).…”

“…Time-dated pregnant SpragueDawley rats were purchased from Charles River Laboratories (Portage, MI). As described previously, the animals were randomly divided into two groups: 1) saline control, and 2) 15 mg/kg cocaine administered intraperitoneally twice daily at 10:00 AM and 4:00 PM from day 15 to 21 of gestational age, the dose that produces plasma cocaine levels in the range of those reported in human cocaine users (2). The animals were allowed to give birth naturally, and no fetal loss in the control and cocaine-treated groups was observed.…”

“…Myocardial infarct size was measured as described previously (2). At the end of reperfusion, the left ventricle was sectioned into four pieces and incubated in 1% triphenyltetrazolium chloride at 37°C for 15 min.…”

“…While the effect of fetal cocaine exposure on birth weight and gross cardiac malformations is still under investigation, recent animal studies in our laboratory have demonstrated that the heart undergoes significant changes at the cellular and genetic levels in response to cocaine exposure (4,39). Fetal cocaine exposure causes myocardial cell apoptosis, resulting in a decreased number of myocardiocytes at birth and increases the heart's sensitivity to ischemia and reperfusion injury in adult male offspring in a sex-dependent manner (2,4). These studies also showed a correlation between a decrease in both total and phosphorylated protein kinase Cε and increased myocardial sensitivity to ischemia in adult male offspring after fetal cocaine exposure (2).…”

“…Our previous studies suggest a possible link between an increased sensitivity to ischemia and decreased levels of activated (phosphorylated) PKCε (2). Because IPC is known to activate PKCε in the myocardium to induce protection from ischemia-reperfusion injury, we investigated the possibility that IPC may rescue the myocardium from the increased ischemic sensitivity induced by fetal cocaine exposure.…”