Adenosine Receptors in Targeted Temperature Management: A New Approach to Cardiac Arrest Therapy

1Bates College, Lewiston, Maine 04240; 2University of Alaska, Fairbanks, Alaska, 99709

This review examines the combined use of the A1 adenosine receptor (A1AR) agonist, N6-cyclohexyladenosine (CHA), and the adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (8-SPT), as a proposed method of targeted temperature management (TTM) for cardiac arrest patients. TTM consists of central inhibition of thermogenesis as well as other body surface cooling mechanisms using the A1AR. Neurological damage caused by cardiac arrest can kill or significantly impair life quality, however, studies of hibernation biology reveal fundamental mechanisms that can be applied to induce hypothermia by attenuating thermogenesis and limiting brain damage. Central activation of adenosine receptors by CHA in the solitary nucleus (NTS) inhibits thermogenesis. Unfortunately, this also results in unwanted cardiovascular effects in the periphery. For this reason, CHA can be administered in tandem with 8-SPT, which cannot cross the blood-brain barrier, to block adenosine receptor activation in the periphery. This review also includes an analysis of the effects of CHA and 8-SPT in the central nervous system (CNS) and peripheral nervous system (PNS). This novel dual administration of A1AR ligands has effectively reached targeted temperatures in rats, guinea pigs, and hamsters, with the hope of being used in clinical cardiac arrest therapy.

Hullavarad et al (2021).pdf217.27 KB