Abstract
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 (Tb) control, we evaluated the influence of every-other-day feeding, dose, drug, and ambient temperature (Ta) on the Tb-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 Tb of 32°C, but responses varied and some rats overcooled to a Tb as low as 21°C at 17.0°C Ta. 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 Tb 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 Tb better than dose or ambient temperature.
Footnotes
- Received March 17, 2017.
- Accepted June 22, 2017.
↵1 Current affiliation: Oregon Health & Science University, Portland, Oregon; Vollum Institute and Oregon Hearing Research Center, Portland, Oregon
↵2 Current affiliation: SomaLogic, Boulder, Colorado.
This work was supported in part by a graduate student fellowship from Alaska Native Science and Engineering Program (to I.R.B.); American Heart Association postdoctoral fellowship (to Z.B.); National Institutes of Health National Institute of Neurologic Disorders and Stroke [Grant R15NS070779]; Alaska Space Grant Program pilot project; and Alaska INBRE P20GM103395.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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