Pharmacological Preconditioning with Diazoxide in the Experimental Hypothermic Circulatory Arrest Model

Abstract

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. 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. 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. 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.