The effects of theophylline (a phosphodiesterase inhibitor-adenosine receptor antagonist) and substrate feeding (Ensure, 250 kcal/235 ml) on cold resistance were studied in seminude males undertaking submaximal (50% maximum O2 consumption), intermittent (34% of total time) exercise in the cold (-5 to 15 degrees C, individually adjusted) for 3 h. Each subject (n = 7) served as his own control and was tested on a weekly schedule. Under control treatment, rectal temperature (Tre) decreased by 0.9 degrees C to approximately 36.2 degrees C after cold exposure, whereas under theophylline and Ensure, the decrease of Tre was only 0.4 degrees C, indicating a significant increase (P less than 0.05) in cold resistance (50% better than control). The plasma concentration of theophylline was 4.8-5.9 micrograms/ml and was positively correlated with plasma concentration of free fatty acids. Plasma norepinephrine (NE) increased significantly during cold exposure; the absolute concentration was significantly higher after theophylline pretreatment. The plasma concentrations of glucose, epinephrine, cortisol, and adenosine 3',5'-cyclic monophosphate did not change and the changes of free thyroxine and triiodothyronine were minor. Together, the effectiveness of theophylline + Ensure in acutely increasing cold resistance may be due to increased substrate availability for thermogenesis, part of which, through theophylline's potentiation of both sympathetic release of NE and NE-stimulated lipolysis and part of which, through supplementary feeding of Ensure.

Richardson's ground squirrels [body temperature (Tb) 7 degrees C] survive prolonged stable hypothermia for three times as long as do rats (Tb 19 degrees C) (72 vs. 24 h). We have examined the changes in blood gases and acid-base state to assess whether these contribute to this difference in survival time. None of the variables (measured at ambient temperature of 25 degrees C) differed significantly between rats and ground squirrels before hypothermic induction. During cooling, neither hematocrit nor plasma lactate changed significantly, but arterial and venous PO2 and PCO2 increased and arterial and venous pH decreased in both groups. During prolonged hypothermia, hematocrit increased significantly in rats (58.8 +/- 1.7% at 24 h) but not in ground squirrels (39.1 +/- 1.0% at 72 h). Both species maintained stable arterial blood gases but showed decreased venous PO2; arterial and venous pH decreased significantly with time in both species in conjunction with increased plasma lactate. These patterns of decreased venous PO2 and increased plasma lactate suggest that reduced tissue oxygenation occurs during hypothermia. This happens earlier in rats at a Tb of 19 degrees C than in ground squirrels at a Tb of 7 degrees C, possibly as a result of increased hematocrit in hypothermic rats. Remedial measures directed at improving tissue O2 delivery may therefore prolong the hypothermic survival of rats.

Impairment of metabolic substrate mobilization and utilization may be a factor limiting survival in hypothermia. Using a newly developed technique for maintaining stable low body temperature (Tb), substrate profiles and their regulation by glucagon were examined in hypothermic rats (Tb 19 +/- 0.3 degrees C) over 20 h. During cooling, plasma glucagon, glucose, and free fatty acid (FFA) concentrations increased significantly (536 +/- 55 pg/ml, 304 +/- 26 mg/100 ml, and 844 +/- 81 mueq/l, respectively). Plasma glucagon and glucose concentrations continued to increase up to 8 h (peaks 810 +/- 103 pg/ml and 451 +/- 33 mg/100 ml, respectively) and remained high throughout the rest of the hypothermic period. FFA concentrations decreased steadily during the hypothermic period. Exogenous glucagon (20 micrograms/kg) induced significant increases in plasma glucose (+129 +/- 31 mg/100 ml) and FFA concentrations (+351 mueq/l) at 2 h but had no effect at 15 h of hypothermia. In vitro evaluation of pancreatic alpha-cell function indicated that glucagon secretion is independent of temperature between 37 and 19 degrees C. Our data indicate that hypothermia is characterized by a disturbed substrate metabolism, which is likely due to an imbalance in pancreatic alpha- and beta-cell function and a time-dependent decrease in tissue sensitivity to glucagon. These deleterious changes may limit survival in hypothermia.