Phenothiazine-Induced Hyperglycemia: Relation to CNS and Adrenal Effects

Abstract

An increase in blood glucose levels after the administration of chlorpromazine has been observed in several animal species including man (1-5). Other phenothiazines have been shown to exhibiit a hyperglycemic response when administered to rats (6). Neither a depression of the motor activity nor a reduced body temperature are decisive factors in the origin of the chlorpromazineinduced hyperglycemia ( 7 ) .Phenothliazine derivatives have been shown to release catecholamines from adrenal glands in vitro (8). The removal of the adrenal glands or the adrenal medulla from rats prevents the hyperglycemic action of chlorpromazine (6). These studies suggest that the primary mechanism of phenothiazineinduced hyperglycemia is through the release of epinephrine from the adrenal glands.Four phenothiazines, with varying CNS activity ( 9 ) ' were compared for their ability to induce hyperglycemia, to produce CNS depression and to release catecholamines from isolated adrenal glands. These stud' lies were done to test the hypothesis that catecholamine release is directly related to the hyperglycemia produced by various phenothiazine compounds. It was also of interest to determine whether the degree of CNS depression produced by these compounds was correlated with the degree of hyperglycemia associated with their use.Materials and Methods. Animals. Male albino mice, weighing 20-24 g (Laboratory Supply Co., Indianapolis), were used in the blood glucose and CNS depression 1This investigation was supported in part by an NIH Grant No. Pol-GM15005. 2 Recipient of Predoctoral Fellowship No. 1-FOl-GM 43, 285-01 from the National Institute of General Medical Sciences, NIH.studies. Prior to experimentation the mice were housed in groups of 20 with free access to food and water. In some experiments, bilateral adrenalectomy was performed 5 days prior to drug treatment and the animals were maintained on a regular diet with 0.9% sodium chloride in the drinking water.Determination of blood glucose. The animals were sacrificed by decapitation. Blood was collected in beakers wetted with oxalate, and then assayed for glucose by the glucose oxidase method?Evaluation of CNS depression. Depression of spontaneous motor activity was determined for groups of 5 mice using circular photocell activity cages (Woodward Research Corp., Herndon, Va.) .Perfusion of isolated adrenal glands. Isolated bovine adrenals were used to obtain a measure of the catecholamine releasing abilities of CPZ and its analogs, since it was not possible to use mouse adrenals for this purpose. Fresh bovine adrenal glands were obtained at a local abbatoir and placed on ice during transport. About 45-60 min postmortem and glands were cannulated through the adrenal vein and perfused in a retrograde manner with aerated Locke's solution (10) at 37". Flow rates were maintained at 5 ml/min using a multichannel metering pump (Harvard Apparatus Col.) . A perfusion period of 45 min was allowed to elapse prior to the addition of the drugs, dissolved in Locke's solution (10 ml). The number of ...

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Antipsychotic-Induced Type 2 Diabetes: Evidence From a Large Health Plan Database

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