Altered thermoregulation via sensitization of A1 adenosine receptors in dietary-restricted rats

Abstract

Rationale Evidence links longevity to dietary restriction (DR). A decrease in body temperature (Tb) is thought to contribute to enhanced longevity because lower Tb reduces oxidative metabolism and oxidative stress. It is as yet unclear how DR decreases Tb. Objective Here, we test the hypothesis that prolonged DR decreases Tb by sensitizing adenosine A1 receptors (A1AR) and adenosine-induced cooling. Methods and results Sprague–Dawley rats were dietary restricted using an every-other-day feeding protocol. Rats were fed every other day for 27 days and then administered the A1AR agonist, N6-cyclohexyladenosine (CHA; 0.5 mg/kg, i.p.). Respiratory rate (RR) and subcutaneous Tb measured using IPTT-300 transponders were monitored every day and after drug administration. DR animals displayed lower RR on day 20 and lower Tb on day 22 compared to animals fed ad libitum and displayed a larger response to CHA. In all cases, RR declined before Tb. Contrary to previous reports, a higher dose of CHA (5 mg/kg, i.p.) was lethal in both dietary groups. We next tested the hypothesis that sensitization to the effects of CHA was due to increased surface expression of A1AR within the hypothalamus. We report that the abundance of A1AR in the membrane fraction increases in hypothalamus, but not cortex of DR rats. Conclusion These results suggest that every-other-day feeding lowers Tb via sensitization of thermoregulatory effects of endogenous adenosine by increasing surface expression of A1AR. Discussion Evidence that diet can modulate purinergic signaling has implications for the treatment of stroke, brain injury, epilepsy, and aging.

Natural Protection Against Cardiac Arrhythmias During Hibernation: Significance of Adenosine

“…Mechanisms involved in induction of hypothermia are under investigation. Results from our studies have shown that DR-induced hypothermia is due to adenosine sensitization (Jinka et al, 2010). Our results have demonstrated that intraperitoneal administration of CHA (0.5mg/kg) in DR-sensitized rats induced a significant cooling undetected in ad libitum (AL) rats.…”

“…These results also suggest that a torpid like effect is seen with CHA-induced hypothermia in DR rats. However, it is not known from these studies as to how the heart responds to this CHA-induced hypothermia in DR rats (Jinka et al, 2010).…”

“…A sudden drop in metabolism followed by a decrease in core body temperature is the hallmark of hibernation (Lyman, 1958). CHA-induced hypothermia in DR rats resembled torpor in hibernators as there is a sudden decrease in respiration, an indicator of metabolism, followed by a slow decrease in body temperature (Jinka et al, 2010). Central administration of CHA in hibernators results in hypothermia without any untoward effects on heart while cardiac arrhythmias were seen with anesthetic-induced hypothermia (Miyazawa et al, 2008).…”

“…DR-induced cooling is well established in various rodents (Conti et al, 2006;Ungvari et al, 2008;Contestabile, 2009). What is novel in the recent research is that adenosine A1 receptor (A 1 AR) agonist; CHA administration induces increased hypothermic response in DR rats (Jinka et al, 2010), although the response of the cardiovascular system is not measured. This CHA-induced hypothermia in DR rats is similar to the torpor seen in hibernation and this is achieved through sensitization of A 1 AR in the brain's hypothalamus, the principle thermoregulatory center in the CNS.…”

Ethical considerations in hibernation research

“…Major surgery is required to implant the intraperitoneal transmitters, but the data obtained show unequivocal patterns of hibernation 6,25–28 . If hibernating animals are housed at ambient temperatures of ≥20 °C, then transponders such as the IPTT-300 (Bio Medic Data Systems, city, state) can be used to monitor body temperature with a telemetry system (DAS-6000; Bio Medic Data Systems) 29,30 . These transponders can be implanted subcutaneously between the scapula without surgery but may not be reliable below 21.4 °C (ref.…”