Diazoxide increases liver and kidney HSP25 and HSP70 after shock and stroke.
BACKGROUND
The compound, diazoxide (DZ), is known to induce preconditioning through its effect as a mitochondrial K(ATP) channel opener and succinate dehydrogenase inhibitor. Our team tested the hypothesis that pharmacological induction of ischemic preconditioning with DZ can offer cytoprotection and preserve vital tissues after hemorrhagic shock and stroke.


METHODS
Sprague-Dawley male rats received an intraperitoneal injection of sterile saline or 5 mg/kg DZ in saline 24 h prior to 1 h of hemorrhagic shock, by approximately 40% total blood loss volume (Shock Study), or a permanent unilateral common carotid ligation just before shock (Stroke + Shock Study). While remaining under isoflurane anesthesia, animals then received 81 mL/kg intravenous sterile saline over the next 45 min for recovery and survived for another 24 h.


RESULTS
When DZ was administered 24 h prior to shock, it significantly reduced hyperglycemia, which in vehicle-treated animals persisted after resuscitation. DZ also attenuated hyperlactatemia during the 1-h shock period. With more severe trauma from combined stroke and shock, DZ also decreased hyperlactatemia and hyperglycemia levels but the reduction was only significant for hyperglycemia. The expression levels of heat shock proteins 25 (HSP25) and 70 (HSP70) were used as biomarkers for response of the kidney and liver to DZ and combined stroke and shock. Compared to vehicle-treated animals, DZ-treated rats subjected to shock and stroke exhibited increased HSP25 and HSP70 in kidney and liver tissue.


CONCLUSIONS
DZ-attenuated physiological indicators of metabolic stress following shock or combined shock and stroke and enhanced the up-regulation of cytoprotective heat shock protein expression.
O'Sullivan
Joseph C
JC
Graduate Program in Neuroscience, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA.
Fu
Dadin
D
Alam
Hasan B
HB
McCabe
Joseph T
JT
D000818:Animals; D003981:Diazoxide / Q000494:pharmacology*; D004195:Disease Models, Animal; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000503:physiopathology; D020521:Stroke / Q000378:metabolism* / Q000503:physiopathology; D014665:Vasodilator Agents / Q000494:pharmacology*
D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D009363:Neoplasm Proteins; D014665:Vasodilator Agents; D003981:Diazoxide