Protecting mitochondrial bioenergetic function

Reversal of cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been ischemic for variables periods of time. However, reperfusion concomitantly activates a myriad of pathogenic mechanisms causing what is known as “reperfusion injury.” At the center of reperfusion injury are mitochondria, playing a critical role as effectors and targets of injury. Mitochondrial injury compromises oxidative phosphorylation and the ability to regenerate Adenosine-5'-triphosphate (ATP); i.e., bioenergetic function. Thus targeting mitochondria to protect bioenergetic function may represent a novel concept in resuscitation with the potential for altering clinical practice. We have identified sodium-hydrogen exchanger isoform-1 (NHE)-1 inhibition and erythropoietin as attractive candidate drugs for this purpose and demonstrated corresponding functional and clinical benefits. Further work on the subject may pave the way for further scientific discover focused on greater understating of underlying cell mechanisms, identification of additional and perhaps more potent strategies, and develop means for effective drug delivery.

cardiac arrest, reper-fusion injury, mitochondria, bioen-ergetic function, left ventricular myo-cardial distensibility, sodium-hydro-gen exchanger isoform-1 (NHE-1) inhibitors, erythropoietin

1. Binak K, Harmanci N, Sirmaci N, Ataman N, Ogan H. Oxygen extraction rate of the myocardium at rest and on exercise in various condi-tions. Br Heart J 1967;29:422-7.

2. Yusa T, Obara S. Myocardial oxygen extraction rate under general anesthesia. Tohoku J Exp Med 1981;133:321-4.

3. Hoffman JIE. Maximal coronary flow and the concept of coronary vascular reserve. Circulation 1984;70:153-9.

4. Duggal C, Weil MH, Gazmuri RJ, Tang W, Sun S, O’Connell F, Ali M. Regional blood flow during closed-chest cardiac resuscitation in rats. J Appl Physiol 1993;74:147-52.

5. Dong Z, Saikumar P, Weinberg JM, Venkatachalam MA. Calcium in cell injury and death. Annu Rev Pathol 2006;1:405-34.

6. Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 2006;34:232-7.

7. Weisfeldt ML, Zweier J, Ambrosio G, Becker LC, Flaherty JT. Evidence that free radicals result in reperfusion injury in heart muscle. Basic Life Sci 1988;49:911-9.

8. Klouche K, Weil MH, Sun S, Tang W, Povoas HP, Kamohara T, et al. Evolution of the stone heart after prolonged cardiac arrest. Chest 2002;122:1006-11.

9. Ayoub IM, Kolarova JD, Yi Z, Trevedi A, Deshmukh H, Lubell DL, Franz MR, Maldonado FA, Gazmuri RJ. Sodium-hydrogen exchange inhibi-tion during ventricular fibrillation: Beneficial effects on ischemic contracture, action potential duration, reperfusion arrhythmias, myocardial function, and resuscitability. Circulation 2003;107:1804-9.

10. Ayoub IM, Kolarova J, Kantola R, Radhakrishnan J, Gazmuri RJ. Zoniporide preserves left ventricular compliance during ventricular fibril-lation and minimizes post-resuscitation myocardial dysfunction through benefits on energy metabolism. Crit Care Med 2007;35:2329-36.

11. Gazmuri RJ. Effects of repetitive electrical shocks on postresuscitation myocardial function. Crit Care Med 2000;28:228-32.

12. Gazmuri RJ, Deshmukh S, Shah PR. Myocardial effects of repeated electrical defibrillations in the isolated fibrillating rat heart. Crit Care Med 2000;28:2690-6.

13. Takino M, Okada Y. Firm myocardium in cardiopulmonary resuscitation. Resuscitation 1996;33:101-6.

14. Sanders AB, Atlas M, Ewy GA, Kern KB, Bragg S. Expired PCO2 as an index of coronary perfusion pressure. Am J Emerg Med 1985;3:147-9.

15. Gudipati CV, Weil MH, Bisera J, Deshmukh HG, Rackow EC. Expired carbon dioxide: A noninvasive monitor of cardiopulmonary resuscita-tion. Circulation 1988;77:234-9.

16. Rubertsson S, Karlsten R. Increased cortical cerebral blood flow with LUCAS; a new device for mechanical chest compressions compared to standard external compressions during experimental cardiopulmonary resuscitation. Resuscitation 2005;65:357-63.

17. Gazmuri RJ, Hoffner E, Kalcheim J, Ho H, Patel M, Ayoub IM, et al. Myocardial protection during ventricular fibrillation by reduction of proton-driven sarcolemmal sodium influx. J Lab Clin Med 2001;137:43-55.

18. Gazmuri RJ, Ayoub IM, Hoffner E, Kolarova JD. Successful ventricular defibrillation by the selective sodium-hydrogen exchanger isoform-1 inhibitor cariporide. Circulation 2001;104:234-9.

19. Gazmuri RJ, Ayoub IM, Kolarova JD, Karmazyn M. Myocardial protection during ventricular fibrillation by inhibition of the sodium-hydrogen exchanger isoform-1. Crit Care Med 2002;30:166-71.

20. Kolarova J, Yi Z, Ayoub IM, Gazmuri RJ. Cariporide potentiates the effects of epinephrine and vasopressin by nonvascular mechanisms during closed-chest resuscitation. Chest 2005;127:1327-34.

21. Kolarova JD, Ayoub IM, Gazmuri RJ. Cariporide enables hemodynamically more effective chest compression by leftward shift of its flow-depth relationship. Am J Physiol Heart Circ Physiol 2005;288:2904-11.

22. Ayoub IM, Kolarova J, Kantola RL, Sanders R, Gazmuri RJ. Cariporide minimizes adverse myocardial effects of epinephrine during resus-citation from ventricular fibrillation. Crit Care Med 2005;33:2599-605.

23. Wang S, Radhakrishnan J, Ayoub IM, Kolarova JD, Taglieri DM, Gazmuri RJ. Limiting sarcolemmal Na+ entry during resuscitation from VF prevents excess mitochondrial Ca2+ accumulation and attenuates myocardial injury. J Appl Physiol 2007;103:55-65.

24. Singh D, Kolarova JD, Wang S, Ayoub IM, Gazmuri RJ. Myocardial protection by erythropoietin during resuscitation from ventricular fibril-lation. Am J Ther 2007;14:361-8.

25. Grmec S, Strnad M, Kupnik D, Sinkovic A, Gazmuri RJ. Erythropoietin facilitates the return of spontaneous circulation and survival in victims of out-of-hospital cardiac arrest. Resuscitation 2009;80:631-7.