EFFECTS OF a AND fl-ADRENERGIC BLOCKERS ON CHLORPROMAZINE-INDUCED ELEVATION OF PLASMA GLUCOSE AND CYCLIC AMP IN FED MICE

The subcutaneous administration of chlorpromazine (CPZ) caused a dose response increase in plasma glucose and cyclic AMP levels in fed male mice. Hex amethonium abolished the elevation of both plasma glucose and cyclic AMP. Pro pranolol did not inhibit the elevation of plasma glucose but inhibited the increase of plasma cyclic AMP. In contrast, phentolamine and yohimbine completely suppressed the elevation of plasma glucose but not that of plasma cyclic AMP. These results indicate that the hyperglycemia due to CPZ was mediated through the stimulation of a-adrenoceptor and on the contrary CPZ increased plasma cyclic AMP through the stimulation of p-adrenoceptor and that the increase in plasma glucose induced by CPZ was independent of the activation of adenylate cyclase and the increased plasma cyclic AMP. In addition, in contrast to phentolamine and yohimbine, phenoxybenzamine was ineffective to prevent the hyperglycemia induced by CPZ. Moreover, a higher dose of dihydroergotamine was required to inhibit the hyperglycemia. Since Courvoisier et al. (1) firstly showed the hyperglycemic effect of chlorpromazine (CPZ), many reports have indicated the ability of CPZ to produce hyperglycemia in several species. Several mechanisms considered to be involved in CPZ-induced hyperglycemia. CPZ has been demonstrated to induce hyperglycemia in rats through the activation of a and/or (3-adrenergic receptors (2-6). Hyperglycemia due to CPZ was reported to be closely related the epinephrine release from adrenal medulla (2, 4-7). Moreover an impaired peripheral utilization of glucose (2, 4), a role of the central nervous system (8) and a cor relation between the hypothermia and the hyperglycemia induced by CPZ (2) were indicated to take part in the mechanism of CPZ action. Nevertheless the detailed mechanism of the CPZ action, particularly the participation of a and 13-adrenergic receptors has not been clearly demonstrated. We demonstrated that an administration of CPZ elevated plasma cyclic AMP levels through the stimulation of adrenergic mechanisms (9). Both catecholamines and glucagon are known to elevate plasma glucose, hepatic and plasma cyclic AMP. Glucagon increases the plasma glucose and cyclic AMP levels through the increase in hepatic cyclic AMP. On the other hand, the mechanism of catecholamine to induce hyperglycemia has not been conclusively defined. Some workers stated that (3-adrenergic receptor might be involved in the hyperglycemia (10-12), while others reported that a-adrenergic receptor might be involved (13-17). These controversial results may be due to differences in experimental conditions (18, 19) and in the animal species (5, 12, 20, 21). We examined the mechanism of the elevation of plasma glucose and cyclic AMP induced by CPZ by using a and (9-adrenergic blockers. Of particular interest was the mechanism of CPZ action, particularly the role of hepatic glycogenolysis in fed mice in which there was no depletion of liver glycogen (18). The results indicated that CPZ increases plasma cyclic AMP through Q-adrenergic receptor and induces hyperglycemia independent of increase in hepatic and plasma cyclic AMP. Moreover, our results also suggest a possible presence of different types of a-adrenoceptors in mice for the regulation of blood glucose. MATERIALS AND METHODS Male ddY mice, weighing 20-30 g were used and the room temperature was kept con stant. CPZ was usually given subcutaneously in a dose of 10 mg/kg to mice allowed free access to food until the experiment. Thirty minutes later the animals were decapitated and the blood was immediately collected. Mice were sacrified at 12:00-14:00 in all experiments. The blood glucose was estimated by means of the glucose oxidase procedure (22) using a kit from Boehringer Mannheim Co., W. Germany. Plasma cyclic AMP was determined using the radioimmunoassay kit from Yamasa Shoyu Co., Choshi, Japan, following the procedure developed by Honma et al. (23). Sources of reagents are as follows: chlorpromazine hydrochloride, Shionogi Phar maceutical Co., Osaka; hexamethonium bromide, Yamanouchi Pharmaceutical Co., Tokyo; propranolol hydrochloride, Sigma Chemical Co. ; phentolamine mesylate, Japan CIBA Geigy, Takarazuka, Japan; yohimbine hydrochloride and phenoxybenzamine hydrochloride, Nakarai Chemicals Ltd., Kyoto; dihydroergotamine tartarate, Sigma Chemical Co. Concentrations of the drug solutions were prepared to allow for administration of volume doses of 10 ml/kg. Doses were calculated on the basis of the salt of each drug. All samples from each experiment were measured within a single assay. Results were evaluated using Student's t-test.