The impact of ascorbate on oxidative stress-related diseases is moderate because of its limited oral bioavailability and rapid clearance. However, recent evidence of the clinical benefit of parenteral vitamin C administration has emerged, especially in critical care. Heatstroke is defined as a form of excessive hyperthermia associated with a systemic inflammatory response that results in multiple organ dysfunctions in which central nervous system disorders such as delirium, convulsions, and coma are predominant. The thermoregulatory, immune, coagulation and tissue injury responses of heatstroke closely resemble those observed during sepsis and are likely mediated by similar cellular mechanisms. This study was performed by using the characteristic high lethality rate and sepsis-mimic systemic inflammatory response of a murine model of heat stroke to test our hypothesis that supra-physiological doses of ascorbate may have therapeutic use in critical care. We demonstrated that parenteral administration of ascorbate abrogated the lethality and thermoregulatory dysfunction in murine model of heat stroke by attenuating heat stroke-induced accelerated systemic inflammatory, coagulation responses and the resultant multiple organ injury, especially in hypothalamus. Overall, our findings support the hypothesis and notion that supra-physiological doses of ascorbate may have therapeutic use in critical care.

Heat stress is exacerbated by global warming and affects human and animal health, leading to heart damage caused by imbalances in reactive oxygen species (ROS) and the antioxidant system, acid-base chemistry, electrolytes and respiratory alkalosis. Vitamin C scavenges excess ROS, and sodium bicarbonate maintains acid-base and electrolyte balance, and alleviates respiratory alkalosis. Herein, we explored the ability of vitamin C alone and in combination with equimolar sodium bicarbonate (Vitamin C-Na) to stimulate endogenous antioxidants and heat shock proteins (HSPs) to relieve heat stress in H9C2 cells. Control, vitamin C (20 μg/ml vitamin C for 16 h) and vitamin C-Na (20 μg/ml vitamin C-Na for 16 h) groups were heat-stressed for 1, 3 or 5 h. Granular and vacuolar degeneration, karyopyknosis and damage to nuclei and mitochondria were clearly reduced in treatment groups, as were apoptosis, lactate dehydrogenase activity and ROS and malondialdehyde levels, while superoxide dismutase activity was increased. Additionally, CRYAB, Hsp27, Hsp60 and Hsp70 mRNA levels were upregulated at 3 h (p < 0.01), and protein levels were increased for CRYAB at 0 h (p < 0.05) and 1 h (p < 0.01), and for Hsp70 at 3 and 5 h (p < 0.01). Thus, pre-treatment with vitamin C or vitamin C-Na might protect H9C2 cells against heat damage by enhancing the antioxidant ability and upregulating CRYAB and Hsp70.