Optimization of Thermolytic Response to A1 Adenosine Receptor Agonists in Rats

Cardiac arrest is a leading cause of death in the United States, and, currently, therapeutic hypothermia, now called 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, limit application and benefit of TTM. Stimulating central nervous system A₁ adenosine receptors (A₁AR) inhibits shivering and nonshivering thermogenesis in rats and induces a hibernation-like response in hibernating species. In this study, we investigated the pharmacodynamics of two A₁AR agonists in development as antishivering agents. To optimize body temperature (T_b) control, we evaluated the influence of every-other-day feeding, dose, drug, and ambient temperature (T_a) on the T_b-lowering effects of N⁶-cyclohexyladenosine (CHA) and the partial A₁AR agonist capadenoson in rats. The highest dose of CHA (1.0 mg/kg, i.p.) caused all ad libitum-fed Animals tested to reach our target T_b of 32°C, but responses varied and some rats overcooled to a T_b as low as 21°C at 17.0°C T_a Dietary restriction normalized the response to CHA. The partial agonist capadenoson (1.0 or 2.0 mg/kg, i.p.) produced a more consistent response, but the highest dose decreased T_b by only 1.6°C. To prevent overcooling after CHA, we studied continuous i.v. administration in combination with dynamic surface temperature control. Results show that after CHA administration control of surface temperature maintains desired target T_b better than dose or ambient temperature.