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Am J Transl Res 2013;5(3):316-326
Original Article
Erythropoietin facilitates resuscitation from ventricular fibrillation by
signaling protection of mitochondrial bioenergetic function in rats
Jeejabai Radhakrishnan, Madhav P Upadhyaya, Matthew Ng, Ari Edelheit, Hawnyeu M Moy, Iyad M Ayoub, Raúl J
Gazmuri
Department of Medicine and Resuscitation Institute at Rosalind Franklin University of Medicine and Science;
Rosalind Franklin University of Medicine and Science; Resuscitation Institute at Rosalind Franklin University of
Medicine and Science; Department of Medicine, Physiology and Biophysics, Resuscitation Institute at Rosalind
Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois 60064, USA; Critical
Care Medicine and ICU, Captain James A. Lovell Federal Health Care Center, 3001 Green Bay Road, North
Chicago, Illinois 60064, USA. Authors contributed equally to this work.
Received March 25, 2013; Accepted April 9, 2013; Epub April 19, 2013; Published April 30, 2013
Abstract: Objective: We previously reported beneficial myocardial effects during chest compression after
administration of high-dose erythropoietin. We hypothesized that erythropoietin also elicits post-resuscitation
myocardial benefits partly linked to protection of mitochondrial bioenergetic function. Methods: Two series of 10
rats each underwent ventricular fibrillation for 10 minutes (series-1) and 8 minutes (series-2) and were
randomized to erythropoietin (5,000 U/kg) or 0.9% NaCl before chest compression. Dobutamine was infused
post-resuscitation in series-2 harvesting their hearts at 120 minutes. Results: During chest compression, a
statistically insignificant trend showing progressively higher coronary perfusion pressure in the erythropoietin
group was observed consistent with previously reported preservation of left ventricular distensibility. Post-
resuscitation, in the absence of dobutamine (series-1) erythropoietin failed to improve post-resuscitation
myocardial function or survival; in the presence of dobutamine (series-2) all rats survived and those treated with
erythropoietin reversed post-resuscitation myocardial dysfunction yielding higher cardiac work index (CWI; 39±3
vs 25±10 mmHg•ml/kg, p<0.01) and higher mean aortic pressure (MAP; 99±4 vs 83±16, p<0.01) at 120 minutes
post-resuscitation. Better myocardial function was associated with lesser increases in plasma cytochrome c,
attaining levels which inversely correlated with CWI (p=0.026) and MAP (p=0.025). Hearts from erythropoietin-
treated rats had higher phosphorylation levels of cytosolic Akt and higher phosphorylation levels of cytosolic and
mitochondrial PKCε and maintained cytochrome c oxidase activity. Conclusion: Erythropoietin activated
mitochondrial protective mechanisms that helped maintain bioenergetic function enabling reversal of post-
resuscitation myocardial dysfunction in the presence of dobutamine. (AJTR1303008).
Keywords: Cardiopulmonary resuscitation, erythropoietin, mitochondrial function, myocardial function, rats,
ventricular fibrillation
Address correspondence to: Dr. Raúl J Gazmuri, Resuscitation Institute, Rosalind Franklin University of
Medicine and Science, 3333 Green Bay Road; North Chicago, Illinois, 60064, USA. Phone: 224-610-3681; Fax:
847-578-3863; E-mail: raul.gazmuri@rosalindfranklin.edu
Original Article
Erythropoietin facilitates resuscitation from ventricular fibrillation by
signaling protection of mitochondrial bioenergetic function in rats
Jeejabai Radhakrishnan, Madhav P Upadhyaya, Matthew Ng, Ari Edelheit, Hawnyeu M Moy, Iyad M Ayoub, Raúl J
Gazmuri
Department of Medicine and Resuscitation Institute at Rosalind Franklin University of Medicine and Science;
Rosalind Franklin University of Medicine and Science; Resuscitation Institute at Rosalind Franklin University of
Medicine and Science; Department of Medicine, Physiology and Biophysics, Resuscitation Institute at Rosalind
Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois 60064, USA; Critical
Care Medicine and ICU, Captain James A. Lovell Federal Health Care Center, 3001 Green Bay Road, North
Chicago, Illinois 60064, USA. Authors contributed equally to this work.
Received March 25, 2013; Accepted April 9, 2013; Epub April 19, 2013; Published April 30, 2013
Abstract: Objective: We previously reported beneficial myocardial effects during chest compression after
administration of high-dose erythropoietin. We hypothesized that erythropoietin also elicits post-resuscitation
myocardial benefits partly linked to protection of mitochondrial bioenergetic function. Methods: Two series of 10
rats each underwent ventricular fibrillation for 10 minutes (series-1) and 8 minutes (series-2) and were
randomized to erythropoietin (5,000 U/kg) or 0.9% NaCl before chest compression. Dobutamine was infused
post-resuscitation in series-2 harvesting their hearts at 120 minutes. Results: During chest compression, a
statistically insignificant trend showing progressively higher coronary perfusion pressure in the erythropoietin
group was observed consistent with previously reported preservation of left ventricular distensibility. Post-
resuscitation, in the absence of dobutamine (series-1) erythropoietin failed to improve post-resuscitation
myocardial function or survival; in the presence of dobutamine (series-2) all rats survived and those treated with
erythropoietin reversed post-resuscitation myocardial dysfunction yielding higher cardiac work index (CWI; 39±3
vs 25±10 mmHg•ml/kg, p<0.01) and higher mean aortic pressure (MAP; 99±4 vs 83±16, p<0.01) at 120 minutes
post-resuscitation. Better myocardial function was associated with lesser increases in plasma cytochrome c,
attaining levels which inversely correlated with CWI (p=0.026) and MAP (p=0.025). Hearts from erythropoietin-
treated rats had higher phosphorylation levels of cytosolic Akt and higher phosphorylation levels of cytosolic and
mitochondrial PKCε and maintained cytochrome c oxidase activity. Conclusion: Erythropoietin activated
mitochondrial protective mechanisms that helped maintain bioenergetic function enabling reversal of post-
resuscitation myocardial dysfunction in the presence of dobutamine. (AJTR1303008).
Keywords: Cardiopulmonary resuscitation, erythropoietin, mitochondrial function, myocardial function, rats,
ventricular fibrillation
Address correspondence to: Dr. Raúl J Gazmuri, Resuscitation Institute, Rosalind Franklin University of
Medicine and Science, 3333 Green Bay Road; North Chicago, Illinois, 60064, USA. Phone: 224-610-3681; Fax:
847-578-3863; E-mail: raul.gazmuri@rosalindfranklin.edu
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