| Summary: | Cardiac arrest is a leading cause of death in the United States and currently, therapeutic hypothermia, now known as targeted temperature management (TTM), is the only recent treatment modality proven to increase survival rates and reduce morbidity for this condition. Shivering and subsequent metabolic stress however, limits application and benefit of TTM. Stimulating CNS A 1 adenosine receptors inhibits shivering and nonshivering thermogenesis in rats and induces a hibernation‐like response in arctic ground squirrels and rats. We found previously that N 6 ‐cyclohexyladenosine (CHA) is more effective at reducing core body temperature (T b ) in dietary restricted (DR) rats than in ad libitum (AL) fed rats. To develop A 1 AR agonists for TTM in AL fed animals, the current study evaluates the effectiveness of dose, drug and ambient temperature (T a ) on the T b lowering effects of CHA and capadenoson in freely fed rats. We found that CHA lowered oxygen consumption (VO 2 ) in AL and DR fed rats, consistent with an inhibition of thermogenesis. CHA at 0.5 or 1.0mg/kg in AL rats produced large variations in response at 17.0°C T a , but after 1.0 mg/kg, IP, all animals cooled to or below a target T b of 32°C; some animals over‐cooled to as low as 21°C but re‐warmed to 37°C without incident at T a 23°C. The partial A 1 AR agonist, capadenoson (1.0 or 2.0mg/kg, IP) produced a consistent response in all animals and decreased T b to a minimum of 36°C from a mean of 38°C at T a 17.0°C during the active phase of the circadian cycle. The response to capadenoson was dose‐dependent . To prevent overcooling after CHA we studied continuous IV administration of CHA in combination with dynamic surface temperature control. Results show this approach to be the best at maintaining a desired target T b . Rigorous optimization of TTM achieved with CHA and dynamic control of conductive cooling will inform future studies aimed at defining the therapeutic benefit of TTM using drugs such as CHA as adjunctive pharmacotherapy. Support or ...
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