Characterization of Cardiac Arrhythmias During n6‐Cyclohexyladenosine Assisted Cooling of Rats
Authors: Dowell Katrina , Barati Zeinab , Laughlin Bernard , Drew Kelly 
Published: November 2023

Drug treatments are needed to facilitate cooling for treatment of cardiac arrest and stroke. A1 adenosine receptor (A1AR) agonist N6‐cyclohexyladenosine (CHA) works in the central nervous system (CNS) to inhibit thermogenesis and induces a torpor‐like state in rats. CHA is in development as a novel thermolytic to facilitate cooling in humans. The drug also has side‐effects on the heart that have not been well characterized. A1AR agonists are known to produce bradycardia, and hypothermia itself produces bradycardia and arrhythmias. The purpose of this research is to characterize the types of arrhythmias during CHA‐induced hypothermia with and without the presence of an adenosine antagonist which cannot pass the blood‐brain barrier. This serves to distinguish between the effects of CHA‐induced hypothermia on the heart and within the brain.

Rats were administered CHA or vehicle (VEH, 25% 8‐hydroxypropyl‐β‐cyclodextrin by continuous IV infusion for 24 h, or CHA + 8‐SPT (8‐(p‐sulfophenyl)theophylline (8‐SPT), an adenosine antagonist lacking the ability to pass the blood‐brain barrier) and placed in a cage equipped with a temperature‐controlled surface. The surface temperature was set to 17°C until the animals reached a target core body temperature (Tb) of 32°C, then was varied around 32°C to maintain the target temperature for 24h. Once the 24h cooling period ended, the surface temperature was gradually increased to 37°C until the animals returned to normothermia (Tb 37°C) with CHA on board. Animals did not reach the target Tb of 32°C unless CHA was administered. ECG was acquired with surgically implanted CTA F40 transmitters (DSI) and Ponemah software. ECG was reviewed from the first 10 min of every hour during baseline (3h), during administration of CHA, CHA + 8‐SPT or VEH (24h each) and during rewarming to a target temperature of 37°C. Arrhythmias were visually inspected in Ponemah software, and the dynamics of the ECG waves were analyzed in Matlab.

CHA‐assisted cooling and rewarming produced core body temperatures between 32–34°C for up to 24h, while VEH administration under identical environmental conditions did not affect body temperature. Types of arrhythmias identified (n=8) include bradycardia, premature ventricular contractions (PVCs), premature atrial contractions (PACs), sinus block, and type II atrioventricular block (Mobitz). Premature atrial contractions were the most common arrhythmia observed during CHA‐assisted cooling. This finding may indicate that activation of CNS A1AR inhibits sinoatrial node through effect on the parasympathetic tone. Sinus block, inverted T‐wave, and Mobitz arrhythmias were observed at a low frequency and isolated in individuals. During CHA‐assisted cooling an increased QRS complex duration and R peak amplitude was observed, and is attributed to the effects of hypothermia on the heart. In the Djungarian Hamster, this indicates slowed ventricular conduction due to decreased core body temperature. Shivering artifact is seen during VEH administration, but is absent during CHA administration. This indicates that CHA blocks the shivering response in rats. Administration of CHA + 8‐SPT reversed bradycardia in cooled rats, however, other arrhythmias present were similar to those seen in CHA only treated animals.

Support or Funding Information

Alaska Space Grant Program, supported by NIH R15 NS070779, supported by The American Heart Association Post‐Doctorate Award # 15POST22850003