Pharmacological Preconditioning with Diazoxide in the Experimental Hypothermic Circulatory Arrest Model
DOI:
https://doi.org/10.1532/hsf.1717Abstract
Background: Hypothermic circulatory arrest includes a remarkable risk for neurological injury. Diazoxide, a mitochondrial adenosine triphosphate–dependent potassium ion (K+ATP) channel opener, is known to have cardioprotective effects. We assessed its efficacy in preventing ischemic injury in a clinically relevant animal model.Â
Methods: Eighteen piglets were randomized into a diazoxide group (n = 9) and a control group (n = 9). Animals underwent 60 minutes of hypothermic circulatory arrest at 18°C. Diazoxide (5 mg/kg + 10 mL NaOH + 40 mL NaCl) was infused during the cooling phase. Metabolic and hemodynamic data were collected throughout the experiment. After 24-hour follow-up, whole brain, heart, and kidney biopsy specimens were collected for analysis.Â
Results: Cerebellar Cytochrome-C and caspase-3 activation was higher in the control group (P = .02 and
P = .016, respectively). Antioxidant activity tended to be higher in the diazoxide group (P = .099). Throughout the experiment, the oxygen consumption ratio was higher in the control animals (Pg = .04), as were the lactate levels
(Pg = .02). Cardiac function tended to be better in diazoxide-treated animals.Â
Conclusion: Diazoxide might confer neuroprotective effect as implied by the immunohistochemical analysis of the brain. Additionally, the circulatory effects of diazoxide were beneficial, supporting its neuroprotective effect.Â
References
Abedin Z, Louis-Juste M, Stangl M, Field J. 2013. The role of base excision repair genes OGG1, APN1 and APN2 in benzo[a]pyrene-7,8-dione induced p53 mutagenesis. Mutat Res 750:121-8.
Bajgar R, Seetharaman S, Kowaltowski AJ, Garlid KD, Paucek P. 2001. Identification and properties of a novel intracellular (mitochondrial) ATP-sensitive potassium channel in brain. J Biol Chem 276:33369-74.
Bell KF, Fowler JH, Al-Mubarak B, Horsburgh K, Hardingham GE. 2011. Activation of Nrf2-regulated glutathione pathway genes by ischemic preconditioning. Oxid Med Cell Longev 2011:689524.
Coetzee WA. 2013. Multiplicity of effectors of the cardioprotective agent, diazoxide. Pharmacol Ther 140:167-75.
Garlid KD, Paucek P, Yarov-Yarovoy V, et al. 1997. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res 81:1072-82.
Gega A, Rizzo JA, Johnson MH, Tranquilli M, Farkas EA, Elefteriades JA. 2007. Straight deep hypothermic arrest: experience in 394 patients supports its effectiveness as a sole means of brain preservation. Ann Thorac Surg 84:759-66; discussion 766-7.
Jensen HA, Loukogeorgakis S, Yannopoulos F, et al. 2011. Remote ischemic preconditioning protects the brain against injury after hypothermic circulatory arrest. Circulation 123:714-21.
Kay L, Rossi A, Saks V. 1997. Detection of early ischemic damage by analysis of mitochondrial function in skinned fibers. Mol Cell Biochem 174:79-85.
Korge P, Honda HM, Weiss JN. 2002. Protection of cardiac mitochondria by diazoxide and protein kinase C: implications for ischemic preconditioning. Proc Natl Acad Sci U S A 99:3312-17.
Kouchoukos NT, Blackstone EH, Hanley FL, Kirklin JW. 2013. Hypothermia, circulatory arrest and cardiopulmonary bypass. In: Cardiac surgery: morphology, diagnostic criteria, natural history, techniques, results and indications. Philadelphia: Elsevier. pp. 67-133.
Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD. 2001. Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria. Am J Physiol Heart Circ Physiol 280:H649-57.
Liu Y, Ren G, O’Rourke B, Marban E, Seharaseyon J. 2001. Pharmacological comparison of native mitochondrial K(ATP) channels with molecularly defined surface K(ATP) channels. Mol Pharmacol 59:225-30.
Mitsuishi Y, Motohashi H, Yamamoto M. 2012. The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism. Front Oncol 2:200.
Mitsumoto A, Nakagawa Y. 2001. DJ-1 is an indicator for endogenous reactive oxygen species elicited by endotoxin. Free Radic Res 35:885-93.
Nakai T, Ichihara K. 1994. Effects of diazoxide on norepinephrine-induced vasocontraction and ischemic myocardium in rats. Biol Pharm Bull 17:1341-4.
Pain T, Yang XM, Critz SD, et al. 2000. Opening of mitochondrial K(ATP) channels triggers the preconditioned state by generating free radicals. Circ Res 87:460-6.
Paucek P, Mironova G, Mahdi F, Beavis AD, Woldegiorgis G, Garlid KD. 1992. Reconstitution and partial purification of the glibenclamide-sensitive, ATP-dependent K+ channel from rat liver and beef heart mitochondria. J Biol Chem 267:26062-9.
Roseborough G, Gao D, Chen L, et al. 2006. The mitochondrial K-ATP channel opener, diazoxide, prevents ischemia-reperfusion injury in the rabbit spinal cord. Am J Pathol 168:1443-51.
Standen NB, Quayle JM, Davies NW, Brayden JE, Huang Y, Nelson MT. 1989. Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science 245:177-80.
Svensson LG, Crawford ES, Hess KR, et al. 1993. Deep hypothermia with circulatory arrest. Determinants of stroke and early mortality in 656 patients. J Thorac Cardiovasc Surg 106:19-28; discussion 28-31.
Trube G, Rorsman P, Ohno-Shosaku T. 1986. Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic beta-cells. Pflugers Arch 407:493-9.
Valavanidis A, Vlachogianni T, Fiotakis C. 2009. 8-hydroxy-2’ -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 27:120-39.
Wang L, Zhu QL, Wang GZ, et al. 2011. The protective roles of mitochondrial ATP-sensitive potassium channels during hypoxia-ischemia-reperfusion in brain. Neurosci Lett 491:63-7.
Zhan RZ, Wu C, Fujihara H, et al. 2001. Both caspase-dependent and caspase-independent pathways may be involved in hippocampal CA1 neuronal death because of loss of cytochrome c From mitochondria in a rat forebrain ischemia model. J Cereb Blood Flow Metab 21:529-40.
