The objective of the proposed research is to determine the mechanisms, metabolic consequences, and functional significance of hypoxia-induced hypothermia. The specific hypotheses to be tested are: . Hypoxia-induced hypothermia in mammals is mediated by arginine vasopressin, caused by depression of the normal thermogenic response to cooling, and augmented by behavioral hypothermia. . Hypoxia-induced hypothermia in ectotherms is mediated by arginine vasotocin, caused by behavioral responses, and augmented by increased cutaneous blood flow. . Hypoxia-induced hypothermia will have a protective effect on high energy phosphate stores and intracellular pH of the brain. . Hypoxia-induced hypothermia will have a long term protective effect on brain function (learning ability) and brain cell integrity. . Hypoxia-induced hypothermia will reduce the severity of tissue hypoxia as evidenced by decreased hypoxanthine levels. . Hypoxia-induced hypothermia will reduce the metabolic and ventilatory responses to graded hypoxia and improve arterial blood gases. If results are positive, hypothermia could be used beneficially in treatment of hypoxemic patients, particularly in pediatric intensive care where standard practice is to maintain normal body temperature. Arginine vasopressin (vasotocin in ectotherms) is hypothesized as the mediator. Mammals (rat and opossum) and a ectothermic vertebrate (toad) will be studied. Control animals (kept at core temp of 37degrees C hypoxia) will be compared with animals permitted to become hypothermic. The hypothesized benefit of hypothermia to brain metabolism and function during hypoxia will be determined by 31P-NMR spectroscopic measurements of high energy phosphates and pH by comparing learning ability of normothermic and hypothermic rats. Significance to the brain region important for spatial learning (hippocampus) will be determined by histological exam. The physiological significance of hypothermia to cardiopulmonary function will be assessed by measuring oxygen uptake, ventilatory responses, and arterial blood gases during graded hypoxia. Hypothesized mediation by AVP (AVT) will be tested using specific antagonists and with the Brattleboro rat (genetically AVP deficient). Hypercapnia will be added in some experiments to augment the hypothermia and simulate asphyxia.
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