The effect of diazoxide upon heat shock protein expression and physiological response to hemorrhagic shock and cerebral stroke /

by O'Sullivan, Joseph C

THE EFFECT OF DIAZOXIDE UPON HEAT SHOCK PROTEIN EXPRESSION AND PHYSIOLOGICAL RESPONSE TO HEMORRHAGIC SHOCK AND CEREBRAL STROKE LTC Joseph C. O’Sullivan Thesis directed by: Joseph T. McCabe, Ph.D., Professor and Vice-Chair of the Department of Anatomy, Physiology and Genetics; and Professor of Neuroscience and Molecular and Cell Biology Our team tested the hypothesis that pharmacological induction of ischemic preconditioning (IPC) can offer cytoprotection and preserve vital tissues after cerebral stroke with hemorrhagic shock. The compound, diazoxide (DZ), is known to mimic IPC through its effects as a mitochondrial KATP channel opener and succinate dehydrogenase inhibitor. The effect of DZ was examined under two IPC protocols: delayed preconditioning and postconditioning in an anesthetized rat model of hemorrhagic shock, combined in some experimental groups with cerebral vascular occlusion (stroke). When DZ was administered 24 hours prior to shock (delayed preconditioning), it significantly reduced hyperglycemia, which in vehicle-treated animals persisted after resuscitation. DZ also attenuated hyperlactatemia during the 1 hour shock period. With more severe trauma from combined stroke and shock, DZ also decreased hyperglycemia, but the apparent reduction of hyperlactatemia did not reach statistical significance. DZ iii also appeared to increase the survival rate of animals that sustained combined stroke and shock, but not significantly (p=.058). The expression levels of heat shock proteins 25 (HSP25) and 70 (HSP70) were used as biomarkers for assessing the response of the kidney, liver, and right cerebral cortex and hippocampus to combined stroke and shock. Compared to vehicle-treated animals, DZ- pretreated rats subjected to stroke and shock exhibited increased HSP25 and HSP70 expression in kidney, liver and brain tissue. When administered in a postconditioning Stroke + Shock model, where DZ was administered at two time points after stroke and shock, DZ again caused a significant increase in HSP25 and HSP70 expression in the ipsilateral cerebral cortex and hippocampus. As a postconditioning trigger, given after stroke and shock, DZ was effective when it was administered 60 minutes after shock immediately prior to reperfusion but not when given 10 minutes after Stroke and Shock (without immediate reperfusion). Taken together, these results suggest DZ attenuates physiological indicators of metabolic stress following shock or combined shock and stroke, that it may increase survivability, and that it enhances the upregulation of cytoprotective heat shock protein expression in key organs. iv