propylthiouracil and Hypothermia

The maintenance of pharmacological torpor and hypothermia (body temperature 28 °C - 33 °C) in rats for a week is presented. For this purpose, our laboratory has developed a device (BioFeedback-2) for the feed-back controlled multiple injections of small doses of a pharmacological composition that we created earlier. On the 7th day, the rat spontaneously come out of the pharmacological torpor, the body temperature returned to normal, and on the 8th day, the animal could consume food and water. The proposed approach for maintaining multi-day pharmacological torpor can be applied in medicine, as well as for protecting astronauts during long missions in space.

Topics: Animals; Body Temperature; Diphenhydramine; Drug Combinations; Drug Delivery Systems; Feedback; Heart Rate; Hypothermia; Injections, Intravenous; Ivabradine; Magnesium Sulfate; Male; Phenothiazines; Propranolol; Propylthiouracil; Rats, Wistar; Reserpine; Serotonin; Telemetry; Torpor

To initiate a state of artificial torpor we suggested a pharmacological multi-targeting strategy for simulation of the physiological pattern of natural hibernation including a significant reduction in heart rate, respiratory rate, body temperature and oxygen consumption as well as a decline in brain activity known as torpor.. We have developed a composition which initiates a pharmacologically induced torpor-like state (PITS-composition), made up of eight therapeutic agents, inert gas xenon and lipid emulsion served as a drug vehicle.. After a single intravenous injection to rats, PITS-composition causes a rapid decline in heart rate followed by a steady decrease in body temperature from about 38.5 °C to 31.5 °C, at ambient temperature of 22 °C-23 °C. The hypothermic state may continue on average for 16-17 h with the subsequent spontaneous return of heart rate and body temperature to the initial values. In the open field test at torpor the motility, rearing and grooming were suppressed but 4-8 days later they were restored.. Suspended animation states, including natural hibernation or pharmacologically induced synthetic torpor are of special attention of medicine, since it may improve survival rate after cardiac arrest, brain hemorrhage and ischemia, and during long-term space traveling. The suggested here multi-targeting strategy made possible to develop the pharmacological composition able, after a single intravenous injection, to initiate long, stable and reversible hypothermia and torpor at room temperature. After the torpor, animals were able to spontaneously restore both physiological parameters, and behavioral reactions.

Topics: Animals; Body Temperature; Brain; Diphenhydramine; Drug Combinations; Heart Rate; Hypothermia; Injections, Intravenous; Ivabradine; Magnesium Sulfate; Male; Oxygen Consumption; Phenothiazines; Phospholipids; Propranolol; Propylthiouracil; Rats; Rats, Wistar; Reserpine; Respiratory Rate; Serotonin; Sorbitol; Torpor; Xenon

Thyroid hormone (TH) is essential for a number of physiological processes and is particularly critical during nervous system development. The hippocampus is strongly implicated in cognition and is sensitive to developmental hypothyroidism. The impact of TH insufficiency in the foetus and neonate on hippocampal synaptic function has been fairly well characterised. Although adult onset hypothyroidism has also been associated with impairments in cognitive function, studies of hippocampal synaptic function with late onset hypothyroidism have yielded inconsistent results. In the present study, we report hypothyroidism induced by the synthesis inhibitor propylthiouracil (10 p.p.m., 0.001%, minimum of 4 weeks), resulted in marginal alterations in excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude in the dentate gyrus measured in vivo. No effects were seen in tests of short-term plasticity, and a minor enhancement of long-term potentiation of the EPSP slope was observed. The most robust synaptic alteration evident in hypothyroid animals was an increase in synaptic response latency, which was paralleled by a failure to maintain normal body temperature under anaesthesia, despite warming on a heating pad. Latency shifts could be reversed in hypothyroid animals by increasing the external heat source and, conversely, synaptic delays could be induced in control animals by removing the heat source, with a consequent drop in body and brain temperature. Thermoregulation is TH- dependent, and anaesthesia necessary for surgical procedures posed a thermoregulatory challenge that was differentially met in control and hypothyroid animals. Minor increases in field potential EPSP slope, decreases in PS amplitudes and increased latencies are consistent with previous reports of hypothermia in naive control rats. We conclude that failures in thyroid-dependent temperature regulation rather than direct action of TH in synaptic physiology are responsible for the observed effects. These findings stand in contrast to the synaptic impairments observed in adult offspring following developmental TH insufficiency, and emphasise the need to control for the potential unintended consequences of hypothermia in the interpretation of hypothyroid-induced changes in physiological systems, most notably synaptic transmission.

Topics: Age of Onset; Anesthesia; Animals; Dentate Gyrus; Excitatory Postsynaptic Potentials; Hippocampus; Hypothermia; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Long-Evans

Propylthiouracil (PTU), an antithyroidal drug that reduces serum L-thyroxine (T4) and 3,5,3'-triiodothyronine (T3), is presumed to lower core temperature (T0) by impairing metabolic thermogenesis. However, it is not understood why PTU-treated animals cannot use behavioral and other thermoeffectors to maintain normal Tc. Male rats were administered PTU in drinking water (0.05 mg/ml) while the following parameters were measured: 1) Tc and motor activity (MA) recorded by radiotelemetry for 24 h at ambient temperatures (Ta) of 10-30 degrees C; 2) selected Ta, MA, and Tc in a temperature gradient; and 3) Tc, MA, and grooming behavior during exposure to heat stress (TH = 34.5 degrees C) for 2 h. PTU reduced serum levels of T4, and T3 by 95 and 60%, respectively. Tc decreased after 3 days of PTU treatment; a 0.5 degree C decrease in Tc persisted throughout the PTU treatment. PTU rats exposed to Ta of 10-30 degrees C maintained a consistent hypothermic Tc during the light phase; however, a deficit in the stability of Tc at night was noted during exposure to 10 degrees C. In the temperature gradient, PTU rats selected warmer Ta, but their Tc was maintained at the same hypothermic levels as observed at fixed Ta values of 15-30 degrees C. Heat stress caused Tc of control rats to increase to 39 degrees C, whereas Tc of the PTU rats was maintained below 38 degrees C. The regulation of Tc at hypothermic levels over a wide range of Ta values and when rats were housed in a temperature gradient indicates that chronic PTU induces a state of regulated hypothermia.

Topics: Animals; Behavior, Animal; Body Temperature; Body Temperature Regulation; Heat Stress Disorders; Hypothermia; Hypothyroidism; Male; Motor Activity; Propylthiouracil; Rats; Thyroxine; Triiodothyronine

Mice given propylthiouracil, a thyroid inhibitor, and fed a diet containing a nontoxic level of rac-1(3)-palmitoyl glycerol showed the hypothermia and mortality expected for a toxic dose, but did not show these signs when linoleate or oleate was added to the diet. Loss of radioiodine from the whole animal and thyroid gland was slower when mice were fed the toxic palmitoyl glycerol diet than when fed the same diet containing 4% safflower oil. However, mice fed the two diets did not differ in the extent of the incorporation of radioiodine, and essentially all was bound to protein in each case. Follicular thyroid cells from mice fed the potentially toxic diet that contained unsaturated fat were normal in appearance. Conversely, cells from mice fed the toxic diet were smaller and more densely stained, showing evidence of glycoprotein inside the cell. These findings show that the thyroid gland is affected by the palmitoyl glycerol diet. However, the thyroid is not the only organ affected, because giving either thyroxine or triiodothyronine had no effect on the toxicity of palmitoyl glycerol.

Topics: Animals; Depression, Chemical; Glycerides; Hypothermia; Iodine Radioisotopes; Male; Mice; Propylthiouracil; Safflower Oil; Thyroid Gland; Thyroid Hormones; Thyrotropin-Releasing Hormone

Dietary administration of propylthiouracil (0.2%) to male Sprague-Dawley rats for a period of 8 weeks induced hypothyroidism and hypotension in these animals. Resting heart rate, body weight, colonic temperature and serum thyroxine (T4) were significantly lower in the treated hypothyroid rats than in the controls. Time-course study indicates that the maximal depression of these parameters occurred about the eighth week of PTU treatment; except T4 level which declined abruptly about the second week and remained steady thereafter. The mechanism(s) of hypotension is (are) unknown but there seems to be an interrelationship between hypothyroidism-induced hypotension and the parameters monitored, since discontinuation of PTU treatment reversed that trend of the response toward control levels.

Topics: Animals; Blood Pressure; Body Weight; Heart Rate; Hypotension; Hypothermia; Hypothyroidism; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroxine; Time Factors

Topics: Antithyroid Agents; Biochemical Phenomena; Biochemistry; Catecholamines; Diagnosis; Drug Therapy; Humans; Hypothermia; Hypothermia, Induced; Iodides; Oxidative Phosphorylation; Propylthiouracil; Thyroid Crisis

Topics: Animals; Anti-Bacterial Agents; Dogs; Gastrointestinal Hemorrhage; Hemorrhage; Hypothermia; Hypothermia, Induced; Mortality; Neomycin; Pancreatic Juice; Pancreatitis; Propylthiouracil; Research; Tetracycline

Topics: Animals; Body Temperature; Dogs; Geriatrics; Hypothermia; Hypothermia, Induced; Injections; Injections, Intravenous; Lung Diseases; Metabolism; Oxygen; Propylthiouracil; Research; Respiratory Function Tests

Topics: Dogs; Hypothermia; Iodides; Iodine; Iodine Isotopes; Metabolism; Perchlorates; Pharmacology; Propylthiouracil; Radioisotopes; Research; Thyroid Gland