J.A. Panuska

Ineffectiveness of dimethyl sulfoxide in altering the permeability of the blood-brain barrier

The failure of DMSO to alter the permeability of the blood-brain barrier has been studied using several polar, nonpolar, hydrophilic, and hydrophobic compounds labeled with selected radioactive isotopes. The metabolites were Na131I, 131I-iodinated human serum albumin, l-[35S]methionine, dl-[ring-2-14C]tryptophan, [U-14C]sucrose, d-[6-14C]glucose, and [4-14C]cholesterol. DMSO was injected intraperitoneally at a dose of 1 g/kg followed after 1 hr by the intracarotid injection of the labeled metabolite. An appropriate volume of saline was substituted for the DMSO in control animals. The brain and one gastrocnemius muscle were removed at selected intervals up to 30 min and the uptake into these tissues was measured. It was found that the permeability of neither the blood-brain barrier nor skeletal muscle was altered by this concentration of DMSO. This dose of DMSO, administered intravenously, frequently caused death and, intraperitoneally, caused muscular twitching, lethargy, and hematuria.

Effect of dimethyl sulfoxide on cooling rates of unrestrained rats

Summary A total of 170 adult rats were exposed to 1°C, 15°C, and 25°C environments following ip injections of 3 to 6 g per kg of DMSO in saline. Shaved subjects receiving 3 g per kg of DMSO in a 1°C environment cooled to a body temperature of 10°C within 239 min; subjects receiving 6 g per kg of DMSO cooled to 10°C in 175 min. Shaved saline controls required 412 min to reach the same temperatures. Unshaved rats in a 1°C environment which were treated with 6 g per kg of DMSO cooled to 10°C within 383 min. Unshaved saline controls failed to become hypothermic. Shaved subjects injected with 6 g per kg of DMSO in an environment of 15°C gave a mixed response, a few maintaining normothermia, some cooling a few degrees and then rewarming, and 50% cooling to environmental temperatures. All controls remained normothermic. At an environmental temperature of 25°C, DMSO-treated animals dropped 3.6°C and then rewarmed. Control subjects remained normothermic. Each DMSO-treated group, therefore, manifested a significant disturbance of temperature regulation.

Regional heterothermy and cardiovascular responses during induced hypothermia in non-hibernated and hibernated woodchucks, Marmota monax

Abstract 1. 1. Immediately prior hibernation enhanced the physiological performance of woodchucks. Marmota monax , during induced hypothermia as compared to non-hibernated woodchucks (NH). 2. 2. Carotid systolic blood pressure was lower in hibernated woodchucks (H) than in NH down to a carotid temperature of 13°C. 3. 3. Carotid temperature at cardiac arrest was lower in H (3.4°C) than in NH (7.3°C). 4. 4. Regional heterothermy was more pronounced in H, with the maximal differential between carotid and colon being 7.8°C in H and 1.5°C in NH. 5. 5. Resistance to cooling was greater in H with a cooling rate (min/kg per °C) of 10.5 for H and 4.3 for NH over a carotid temperature range of 30–10°C.

The effect of dimethylsulfoxide on oxygen consumption in cold-exposed rats and hamsters*†

Summary The O 2 consumption of unrestrained rats and hamsters was measured in an open circuit metabolism system during 3 hrs of exposure to an ambient temperature of 4–7°C. Both rats and hamsters which were treated with 3 or 6 g per kg of DMSO intraperitoneally consumed significantly less O 2 than saline controls during the entire test period. The body temperatures of both rats and hamsters which received 3 g per kg of DMSO fell to below control levels but remained higher than the body temperatures of subjects receiving 6 g per kg of DMSO. O 2 consumption did not manifest this dose dependence. The results are interpreted as indicating that the depression of body temperature which follows DMSO treatment of the type described is at least partially due to an inhibition of the normal thermogenic response required for thermal homeostasis.

Dimethylsulfoxide and thermoregulation: Studies on body temperature, metabolic rate and thyroid function

Abstract It has been demonstrated that intraperitoneal injections of DMSO to rats results in a dose-dependent transient depression of thyroid function which is both dose and time correlated with similar effects on body temperature and metabolic rate. At this time, no cause and effect relationships have been established for these effects of DMSO. However, the evidence indicates that the DMSO-treated animals did not elicit a number of normal responses for maintaining body temperature within the homeothermic range. Since these responses are coordinated by hypothalamic control, it has been suggested that the actions of DMSO on thermoregulation might be at that level.

Righting reflexes and spontaneous locomotor activity during hypothermia.

Summary Righting reflexes were tested, and spontaneous locomotor activity was measured in unanesthetized small mammals during the induction of progressive hypothermia. The body-on-body-righting reflex was lost by the guinea pig at a body temperature of 29.2 ± 0.8 (S. E.) °C, the neck-righting reflex at 25.3 ± 0.5°C, and the labyrinthine-righting reflex at 21.8 ± 0.6°C. The neck-righting reflex ended at 16.9 ± 1.6°C in the hamster. Spontaneous locomotor activity was suppressed in the rat at a body temperature of 20.7 ± 0.1°C, 3 to 4°C below the body temperature at which trained performance has been reported to be suppressed in that species.

Failure of heat reinforcement performance by trained animals during hypothermia.

Abstract Shaved, euthermic, male Long-Evans rats weighing 248 ± 29 g, in a 2 °C environment, were trained to obtain external heat from an overhead heating lamp by lever pressing. Steady performance for heat began after 2.0 ± 1.2 hr of exposure to the experimental situation and continued for the remainder of a 19-hr training session. Following the training session, heat loss was increased by moistening the skin of the animals and reducing the duration of the heat reinforcement from 4 sec to 1 3 sec. This effected a progressive hypothermia. Even though the rate of working for external heat increased greatly under this stress, the colonic temperature dropped 1 °C every 13.1 min. When the body temperature reached 25.5 ± 1.0 °C, heat reinforcement performance began to slow down. At 24.6 ± 1.0 °C, this performance stopped, several degrees above the onset of motor failure. This observation was supported by three additional series of experiments involving variations in the duration of training, periods of rest before testing in hypothermia, and means of achieving hypothermia. The body temperature of 24.6 ± 1.0 °C at which previously trained animals failed to perform corresponds closely to a reported critical level for instrumental response acquisition by untrained animals.

Cardiovascular and respiratory function of hypothermic rabbits, as influenced by dimethyl sulfoxide

Abstract This study was conducted to assess the in vivo effect of DMSO on cardiovascular and respiratory functions of a mammal undergoing progressive hypothermia. Parameters investigated included: cardiac output (Fick principle: oxygen consumption, arterial, and venous pO 2 ), arterial pressure, ECG, respiratory rate, and blood pCO 2 and pH. Urethan-anesthetized, shaved, male albino rabbits were used. Fifty animals were injected intra-arterially with a 1-g per kg or 2-g per kg dose of DMSO as a 25% solution in saline, or with saline alone as control. Hypothermia was induced by placing the animals in a chamber at 4 °C and by increasing air movement. Recordings were made at selected body temperatures from normothermia to deep hypothermia. A typical hypothermia-induced cardiovascular depression occurred, which was not altered by DMSO treatment. The cardiac arrest temperature range was 10 to 14 °C, with no significant difference between control and experimental subjects. DMSO-treated animals did not, however, exhibit the increases in respiratory rate and oxygen consumption in the early stages of hypothermia which were present in the controls. This response could be due to an interference with shivering thermogenesis. In animals treated with 2 g per kg DMSO, respiration decreased and pCO 2 increased significantly faster than in control subjects, as the hypothermia progressed.

The effect of dimethyl sulfoxide on heart rate and cardiac arrest in unanesthetized rats during progressive hypothermia.

Summary Rats of two different weight ranges were given saline or dimethyl sulfoxide (DMSO), 6 g per kg in saline, intraperitoneally and exposed to a 2°C environment. During the progressive hypothermia of these unanesthetized and relatively unrestrained subjects, electrocardiograms were recorded by chronically implanted electrodes. Heart rates of lighter animals were faster than heart rates of heavier animals throughout the cooling process. Body temperatures fell more rapidly in DMSO-treated subjects than in saline controls, but DMSO had no effect on the heart rate during the cooling process and also did not change the body temperature at which cardiac arrest occurred.