The role of ethanol in diluents of drugs that protect mice from hypoxia.

Abstract

SUMMARY This study evaluates the hypothesis that ethanol alone, or in diluents for drugs used to protect hypoxic mice, is responsible in part for an increased tolerance to hypoxia (4-5% oxygen). The change in hypoxic tolerance following i.v. or i.p. administration of ethanol, diazepam, nimodipine and various diluent components was measured. Diazepam (50 mg/kg i.v.) increased hypoxic tolerance to 700 ± 47% (n = 11) of saline control, its diluent increased hypoxic tolerance to 468 ± 60% (n = 10) of saline control but the ethanol component of the diluent accounted for almost half of this diluent effect. Nimodipine (2 mg/kg i.p.), a calcium antagonist, increased tolerance to 180 ±18% of control (n = 19) and nimodipine diluent showed an even greater increase to 226 ±25% of control (n = 15). In this case essentially all of the protective effect of nimodipine diluent (81.3%) is accounted for by ethanol. Dose response curves indicate the maximum ethanol induced increase in hypoxic tolerance was approximately 335% of control at a dose of 2.4 g/kg. Buffers, etc. in the diluents evidently add to the protective effect of ethanol. Our data clearly indicate ethanol is the important component of some treatments which protect mice from hypoxia. The pharmacological activity of ethanol, even when used in a diluent, should not be ignored in evaluating therapeutic intervention for protection from hypoxia. Stroke Vol 14, No 5, 1983THE INCREASED SURVIVAL TIME in mice sub jected to hypoxia has been investigated in several labo ratories to identify procedures which may be of thera peutic value in cerebral hypoxia. The importance of these experiments stems from the high morbidity and mortality associated with cerebral hypoxia. The brain appears to be particularly sensitive to hypoxia presum ably because of its high metabolic rate, relatively small stores of high energy phosphates and glucose as well as a relatively low capillary density.1 Although the cause of death or sequence of events leading to death in the hypoxic mouse model have not been established there is evidence to suggest that during hypoxia the cessation of spontaneous ventilation results from reduced brain activity. Recent work in our laboratory using a Levine rat preparation, which includes on-line monitoring of blood pressure, heart rate, respiratory rate, central ve nous pressure and electroencephalogram, indicates that loss of cerebral electrical activity invariably pre cedes loss of spontaneous respiration and ultimate loss of cardiac activity 2 when an animal is exposed to hy poxia. In contrast it has been shown that cardiac func tion is maintained during hypoxia because coronary blood flow is increased by local mechanisms in order to maintain a relatively constant myocardial oxygen tension. 3Clinically, hypoxia may be encountered at high altitudes, 4 during childbirth, deep-sea diving, as a complication during surgery, with a sedative over dose, or because of carbon monoxide poisoning. Fur thermore, hypoxia has been identified as an avoidable extracranial factor as...

Beneficial effect of 1,3-butanediol on cerebral energy metabolism and edema following brain embolization in rats.

“…22 Depressant agents are known to exert protective effects in hypoxic and ischemic situations by reducing the cerebral metabolic rate, and ethanol has been reported to prolong survival in hypoxic mice. 23 However, our results indicate that ethanol, unlike butanediol, does not prevent the development of edema secondary to embolization and are consistent with those of other studies that reported no beneficial effect of ethanol in various models of brain injury. Pretreatment with 47 mmol/kg ethanol, unlike pretreatment with butanediol, did not increase survival time in the Levine rat model, 24 and high doses of ethanol (87 mmol/kg) potentiated traumatic spinal cord and cerebral hemisphere damage in cats.…”

Elevated blood ketone and glucagon levels cannot account for 1,3-butanediol induced cerebral protection in the Levine rat.

“…Alcohols, specifically ethanol, have been reported to have cerebral protective actions. 9 However, ethanol did not significantly increase hypoxic survival time although the average survival time of the ethanol group tended to be higher than that of the saline controls. Butanediol-treated animals had a significantly longer hypoxic survival time compared with either the ethanol group or saline control group.…”