The positive outcome that hypothermia contributes to neuroprotection following brain ischemia has stimulated recent clinical interest in the development of techniques to induce a hypothermic and hypometabolic state. As demonstrated in hibernating animals, we recently showed that hypothermia and a torpor-like state can be induced in rat by central activation of A1AR. Both the reduction in metabolism and the reduced cortical function (i.e., lower EEG amplitude) are of interest in the application of a pharmacological approach to induce hypothermia to ameliorate the outcomes of ischemic stroke. The central activation of A1AR in rat is, however, accompanied by cardiovascular events, such as skipped beats and transient deep bradycardia associated with strong neck muscle activation. Similar events have been reported during naturally occurring torpor. Here we tested the hypothesis that these events arise from vagal input to the heart, by determining the effect of the muscarinic antagonist, atropine. Wistar male rats were implanted with a telemetric probe for the recording of the arterial pressure, with a thermistor located in the mediastinic cavity for the recording of core temperature and electrodes for the recording of the EEG and nuchal EMG. Following a day of baseline recording, rats were placed in an ambient temperature of 15 °C and treated with N6-Cyclohexyladenosine (CHA, 1 mM, 10 μL, ICV) to induce hypothermia. One hour after the injection, animals were treated with intraperitoneal injection of atropine or saline. Our preliminary result showed that atropine prevented the occurrence of the transient bradycardic events and skipped beats, but not the muscular contraction. This result suggests a role of cardiac vagal transmission in driving these cardiovascular events. Our conclusion that treatment with a cholinergic blocker could eliminate this cardiovascular side effect during a deep hypothermic state will support the translational potential of this approach for induction of hypothermia for human use following ischemic stroke.
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