Oxidative stress mediates cardiac infarction aggravation induced by intermittent hypoxia.

We have previously shown that chronic intermittent hypoxia (IH), a component of the obstructive sleep apnea syndrome, increases heart sensitivity to infarction. We investigate here the deleterious mechanisms potentially involved in the IH-induced infarction aggravation, investigating the role of oxidative stress. Male Wistar rats were subjected to chronic IH or normoxia (N). IH consisted of repetitive 1-min cycles (30 s with inspired O2 fraction 5% followed by 30 s normoxia) and was applied for 8 h during daytime, for 14 days. After the 14-day exposure, mean arterial blood pressure (MABP) was higher in the hypoxic compared with the normoxic group. Infarct size, measured on isolated hearts after ischemia-reperfusion, was significantly increased in IH compared with normoxic group (36.0 ± 2.8% vs. 21.8 ± 3.1% for tempol corresponding control groups and 40.3 ± 3.5% vs. 29.4 ± 3.7% for melatonin corresponding control groups). Tempol or melatonin administration during the 14-day IH exposure prevented both IH-induced increase in MABP and infarction aggravation (24.8 ± 2.8% vs. 25.9 ± 4.0% for tempol-treated groups and 32.3 ± 3.2% vs. 34.5 ± 4.2% for melatonin-treated groups). Myocardial oxidative stress was induced by IH, as measured by dihydroethidium (DHE) level and p47-phox expression (the cytosolic protein required for the activation of the NADPH oxidase). This effect was abolished by tempol and melatonin treatments, which were able to normalize DHE level and NADPH expression. In conclusion, oxidative stress appears to mediate the deleterious cardiovascular effects of IH and, in particular, the increased myocardial susceptibility to infarction.

Erythropoietin improved initial resuscitation and increased survival after cardiac arrest in rats.

INTRODUCTION: Recent data have demonstrated potent cardioprotective and neuroprotective effects of the application of growth hormones like erythropoietin (EPO) after focal cardiac or cerebral ischemia. In order to assess possible benefits regarding survival and resuscitation conditions, EPO was tested against placebo in a model of cardiac arrest in the rat. METHODS: Thirty-four male Wistar rats were randomized into two groups (EPO versus control; n=17 per group). Under anesthesia, cardiac arrest was induced by asphyxia after neuromuscular blockade. After 6 min of global ischemia, animals were resuscitated by external chest compression combined with epinephrine administration. An intravenous bolus of recombinant human EPO (rhEPO, 3000 UIkg(-1) body weight, i.v.) or saline (in control group) was performed 15 min before cardiac arrest, by a blinded investigator. Restoration of spontaneous circulation (ROSC), survival at 1, 24, 48 and 72 h and hemodynamic changes after cardiac arrest were studied. RESULTS: Survival to 72 h was significantly improved in the EPO group (n=15/17) compared to the control group (n=7/17). All the EPO-treated rats were successfully resuscitated whereas only 13 of 17 control animals resuscitated. EPO-treated animals required a significantly smaller dose of epinephrine before resuscitation, compared to control rats. Time course of systolic arterial blood pressure after resuscitation revealed no significant differences between both groups. CONCLUSION: EPO, when administrated before cardiac arrest, improved initial resuscitation and increased the duration of post-resuscitation survival.

Erythropoietin pretreatment protects against acute chemotherapy toxicity in isolated rat hearts.

The use of chemotherapeutic agents, such as anthracycline or trastuzumab, in oncology is limited by their cardiac toxicity. Recent experimental studies suggest that recombinant human erythropoietin (rhEPO) can be considered as a protective agent because its administration protects against cardiac ischemic injury, improving functional recovery, and reducing cell death. The aim of this study was to investigate whether pretreatment by rhEPO protects against acute cardiotoxicity induced by doxorubicin and trastuzumab, using the isolated rat heart model. Rats were treated with rhEPO (5000 IU/kg, intraperitoneally [i.p.]) or vehicle. One hour later, hearts were isolated and retrogradely perfused at constant flow. Following 20 mins of stabilization, hearts were perfused for 60 mins with modified-Krebs solution containing 6 mg/l doxorubicin or 10 mg/l trastuzumab. Hearts receiving doxorubicin were paced; those receiving trastuzumab were unpaced. Control hearts were perfused with modified-Krebs solution only. Doxorubicin exposure decreased left ventricular developed pressure (LVDP; approximately -40% of baseline) and increased end diastolic pressure (EDP; approximately +390% of baseline) and coronary perfusion pressure (CPP; approximately +70% of baseline). Incidence of ventricular tachycardia or fibrillation (VT/VF) was also significantly enhanced (86% vs. 0% in control group). Trastuzumab exposure increased CPP and EDP (approximately +70% of baseline for the both) without affecting LVDP. Prior rhEPO treatment significantly prevented doxorubicin-induced deleterious effects on LVDP, EDP, and VT/VF incidence. rhEPO administration also prevented trastuzumab-induced deleterious effects on CPP and EDP. This study shows that pretreatment by rhEPO protects myocardium against functional damage and electrophysiologic injury induced by acute doxorubicin or trastuzumab exposure. Further investigations are required to elucidate the precise mechanisms involved.