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 A(1) adenosine receptors (A(1)AR) 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 A(1)AR 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 N-6-cyclohexyladenosine (CHA) and the partial A(1)AR 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 degrees C, but responses varied and some rats overcooled to a T-b as low as 21 degrees C at 17.0 degrees 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 degrees C. To prevent over-cooling 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.