The effect of adenosine A2A receptor antagonist istradefylline on multiple organ dysfunction in heatstroke rats

Background: Global warming increases the incidence of heatstroke, which is the most severe heat illness. The mortality in patients with heatstroke is due to neurological disability and multiple organ failure caused by systemic inflammatory response. Adenosine A2A receptor antagonist has both neuroprotective and anti-inflammatory effects. Thus, we examined whether a new A2A receptor antagonist istradefylline has beneficial effects in heatstroke rats. Methods: Wistar rats were divided into four groups: (1) control group, with vehicle only (intravenous [iv] for 10 min); (2) control + istradefylline group, with 0.3 mg/kg istradefylline (iv for 10 min); (3) heatstroke group, rectal temperature reached 44.1°C, and then returned to room temperature with vehicle (iv for 10 min); and (4) heatstroke + istradefylline group, rectal temperature reached 44.1°C, and then returned to room temperature with 0.3 mg/kg istradefylline (iv for 10 min). During the experimental period, rectal temperature, heart rate, blood pressure, and pressor responses to norepinephrine (NE) were monitored. Before and after the rats were put into heating chamber, and after the rats returned to room temperature for 6 h, their blood was taken to analyze creatine kinase, lactate dehydrogenase, blood urea nitrogen, creatinine, alanine transaminase, albumin, total protein, and platelet count. In addition, the blood flow of tongue, left limb, and right limb was also monitored. Finally, we examined their survival rate. Results: In the present study, heatstroke rats showed high core body temperature accompanied with cardiac abnormalities and multiple organ dysfunction, mimicking the clinical manifestations of heatstroke patients. Treatment of heatstroke rats with istradefylline only partially improved platelet loss and vascular hyporeactivity to NE. However, istradefylline had no significant effects on cardiac abnormalities and multiple organ dysfunction in rats with heatstroke. Conclusions: These results suggest that although istradefylline has a mild impact on abnormal platelet count and pressor response to NE in heatstroke, both effects are unlikely to counteract multiple organ dysfunction and the mortality.