Effect of acute soman on selected endocrine parameters and blood glucose in rats.

The effects of acute doses of soman (40, 60, or 80 micrograms/kg sc) in rats were evaluated for toxic symptoms as well as for changes in plasma levels of glucose, insulin, glucagon, corticosterone, norepinephrine, and epinephrine. The relationship between changes in these levels and depressed acetylcholinesterase activity in the hypothalamus was determined. Soman 40 micrograms/kg did not manifest significant changes in any of the parameters evaluated. However, both the 60 and 80 micrograms/kg doses of soman caused dose- and time-related increases in plasma levels of glucose, corticosterone, norepinephrine, epinephrine, and a depression of insulin. Many of these increases, as well as the severity of toxicity, appear to be inversely related to the hypothalamic acetylcholinesterase levels. The hyperglycemia following the higher doses of soman is likely due to the combined effects of elevated levels of corticosterone, catecholamines, possibly glucagon, and depressed insulin levels. Stress from the toxic effects of soman is likely partially responsible for the endocrine effects since most of the changes observed are consistent with changes in these levels that would be manifested in an animal stress model.

Effect of repeated administration of soman on selected endocrine parameters and blood glucose in rats.

The effects of repeated administration of soman on plasma glucose levels, acetylcholinesterase (AChE) activity in erythrocytes and hypothalamus, and plasma levels of corticosterone, glucagon, insulin, epinephrine, and norepinephrine were studied in male rats. Rats were given soman subcutaneously (sc), either 30 micrograms/kg every 24 hr for 5 or 12 days or 40 micrograms/kg every 24 hr for 5 days. All doses of soman markedly depressed AChE activity in the hypothalamus and completely inhibited AChE activity in erythrocytes. Soman 30 micrograms/kg given for 5 days did not alter plasma levels of any hormone assayed and produced few signs of intoxication. Soman 40 micrograms/kg given for 5 days elevated plasma levels of glucose and corticosterone and produced signs of severe cumulative intoxication. Daily administration of 30 micrograms/kg of soman for 12 days inhibited hypothalamic AChE activity 75%, lowered plasma insulin, and produced signs of moderate intoxication. Repeated administration of soman produced endocrine alterations only when significant signs of intoxication were evident. The absence of increases in plasma levels of catecholamines and corticosterone in rats exhibiting signs of moderate intoxication, and of catecholamines in rats exhibiting signs of severe intoxication, may indicate an impairment by soman of the normal endocrine response to stress.

Effects of the acetylcholinesterase inhibitor pinacolyl methylphosphonofluoridate (soman) on selected endocrine, glucose, and catecholamine levels in fasted and fed rats.

Fed and 18-h fasted rats were given acute doses of either saline or the acetylcholinesterase inhibitor pinacolyl methylphosphonofluoridate (soman) 40, 60, or 80 micrograms/kg. After 30 min plasma samples were collected and assayed for glucose, insulin, glucagon, corticosterone, epinephrine and norepinephrine and the hypothalamus was isolated and assayed for acetylcholinesterase activity. Toxic sign scores were determined and they indicated that soman may be more toxic in the fasted rat. Soman-induced increases in corticosterone were observed in both fasted and fed rats; these levels were significantly higher in fasted rats given either soman or saline. Also, soman-induced increases in glucagon were more pronounced in fasted rats. Soman also caused an apparent dose-dependent increase in catecholamines and a decrease in hypothalamic acetylcholinesterase activity in both groups of rats. The expected lower insulin and glucose levels in the fasted rats were present in the saline-dosed animals and remained lower than fed rats after each dose of soman. This lack of soman-induced hyperglycemia may contribute to the toxicity of soman in fasted rats.

Effect of hydrocortisone on terbutaline stimulated insulin release from isolated pancreatic islets.

Subchronic treatment with hydrocortisone (HC; 125 mg/kg, ip) in the rat for seven days significantly increased plasma insulin levels without affecting plasma glucose concentrations or insulinogenic indices. The role of the beta-adrenergic activity of the pancreatic beta cells in HC-induced hyperinsulinemia was assessed by determining if HC treatment would potentiate beta-adrenergic agonist-stimulated insulin release from isolated rat islets. Terbutaline (TB; 10(-3)M) and isolated islets from fasted rats were used to test this hypothesis since TB significantly increased insulin release in 300 mg/dl glucose-containing medium (HGM) from the islets of fasted but not of fed rats. Pancreatic islets from overnight-fasted control and HC-pretreated rats were incubated in HGM or HGM containing either 10(-3)TB, 10(-6)M HC, or both TB and HC. It was found that glucose-stimulated and TB-induced insulin release from HC-pretreated rat islets were not different from those of control rat islets. HC (10(-6)M) added in vitro did not affect glucose-stimulated or TB-induced insulin release from the islets of either control or HC-treated rats. In summary, it was found that the insulinotropic effect of TB depends on medium glucose concentration and the nutritional state of animals. However, the results do not support the hypothesis that the hyperinsulinemia caused by subchronic treatment with HC involves enhancement of the beta-adrenergic activity of the pancreatic beta cells.

2-Deoxyglucose tissue levels and insulin levels following tolazamide dosing in normal and obese mice.

The effect of tolazamide (TZ), a sulfonylurea, on 14C-2-deoxyglucose (14C-2DG) tissue distribution and insulin levels of normal and obese mice was investigated using an in vivo physiological method. Acute doses of TZ (50 mg/kg ip) increased 14C-2DG levels in gastrocnemius muscle and retroperitoneal fat and produced a transient elevation of insulin which most likely accounts for the increased 14C-2DG levels in muscle and fat. The results demonstrate that the in vivo 14C-2DG method produced results consistent with known actions of sulfonylureas on in vitro hexose assimilation in muscle and fat. Subchronic treatment (7 days) with TZ 50 mg/kg ip twice daily did not result in increased insulin-stimulated 14C-2DG tissue levels in normal mice when compared to saline treated controls. However, insulin levels were lower in mice treated subchronically with TZ compared to saline controls suggesting an enhancement of insulin action. Viable yellow obese mice represent a model of maturity onset obesity presenting with insulin resistance. The insulin resistance of this obese strain appears to reside in the fat tissue as assessed by comparing 14C-2DG tissue levels of obese mice with lean littermate controls. Subchronic TZ treatment had no effect on 14C-2DG uptake in fat or muscle tissue of viable yellow obese mice and did not alter their plasma insulin levels. It appears that genetically obese viable yellow mice may be resistant to subchronic treatment with TZ.

Effects of noncatechol sympathomimetics on glucose output by hepatocytes from normal and dexamethasone-treated rats.

Isolated hepatocytes from collagenase-perfused rat livers were used to study the hyperglycemic potential of various noncatechol sympathomimetics (NCSPM) commonly found in commercially available cough/cold preparations. The effect of various concentrations of ephedrine, pseudoephedrine, and phenylpropanolamine on glucose output were compared in dexamethasone- or saline-pretreated rats. The NCSPM produced minimal or no glucose output at most of the concentrations tested in hepatocytes from normal saline pretreated rats. However, these same compounds were able to stimulate a significant increase in glucose output from hepatocytes pretreated with dexamethasone. The results indicate that corticosteroids can enhance the glycemic potential of characteristically weak, indirectly acting NCSPM.

The effect of insulin and hydrocortisone on the in vivo tissue uptake of 2-deoxyglucose in mice.

The purpose of this study was to assess the feasibility and limitations of using the uptake of 14C-2-deoxyglucose (14C-2DG) under nonsteady-state conditions in the conscious mouse as a screening model for detecting changes in glucose uptake. Male, Swiss--Webster mice were administered an i.v. dose of 2-deoxyglucose (2DG, 50-75 mg/kg) with 14C-2DG (20 microCi/kg, 44-66 microCi/mmole). The levels of 14C-2DG were measured in gastrocnemius muscle, retroperitoneal fat, liver, cerebral cortex, and blood. Insulin (2 U/kg) s.c. significantly reduced 2DG levels in blood and liver compared to saline controls but significantly increased 2DG levels in muscle and fat. There was no effect on cerebral cortex 2DG uptake. Hydrocortisone (HC) treatment (300 mg/kg, i.p.) significantly reduced brain and muscle 2DG uptake. The effect of HC on brain 2DG levels may be caused by an indirect effect since determination of the 14C-sorbitol space indicated that HC reduced sorbitol levels in the brain when compared to saline controls, a reduction not detected in muscle. The limitations of the model seem to involve the brain and liver. Increasing glucose concentrations (i.v. glucose challenge) lead to decreased 2DG brain levels. It also appears that 2DG may not be reflecting glucose assimilation in the liver. However, it appears that the in vivo 2DG uptake model is a useful screening method for detecting changes in 2DG assimilation in fat and muscle following drug treatment.

Insulin release after acute hydrocortisone treatment in mice.

This investigation examined a potential mechanism for the inhibition of insulin release following an acute dose of hydrocortisone sodium succinate (HC). Hydrocortisone (300 mg/kg intraperitoneally) elevated plasma glucose levels (P less than or equal to 0.05) when administered to male Swiss-Webster mice, without altering plasma insulin levels. This results in a significantly lower insulinogenic index (P less than or equal to 0.05). Hydrocortisone suppressed the glucose-stimulated insulin levels (P less than or equal to 0.05) following an intravenous glucose challenge (2 g/kg) in both fed and fasted mice. Pretreatment with chlorisondamine (EC) and phentolamine (PT) did not alter the HC-induced hyperglycemia but did result in higher plasma insulin levels in response to the higher glucose levels. Adrenalectomy did not prevent the HC-depressed insulin response to hyperglycemia. This is consistent with the hypothesis that an acute dose of HC may be indirectly suppress insulin release by central activation of the sympathetic nerves at the pancreatic islets.

Centrally mediated drug-induced hyperglycemia in mice.

In mice, the hyperglycemic response to a stress, such as repeated orbital puncture, evoked a hyperglycemia through activation of the adrenal medulla and consequent release of catecholamines. This hyperglycemia could be blocked by pretreatment of the mice with the ganglionic blocking agent, chlorisondamine. The hyperglycemic response evoked by single doses of serotonin receptor blocking agents, such as cyproheptadine and methysergide, or by dopamine receptor blockings drugs, such as haloperidol or chlorpromazine, could also be blocked by pretreatment with chlorisondamine. Administration of a single dose of the muscarinic agonist, oxotremorine, also resulted in a hyperglycemia that was blocked by chlorisondamine. The results are compatible with the hypothesis that the adrenal medulla is under the control of a central cholinergic pathway with dopaminergic and serotonergic modulating systems.

Glycemic response to selected sympathomimetics in stressed normal and goldthioglucose mice.

Single intraperitoneal doses of phenylephrine (PE), phenylpropanolamine (PPA) and pseudoephedrine (PSD) have differing effects on blood glucose in stressed, normal and goldthioglucose (GTG) mice. PE in normal and GTG mice caused a pronounced but temporary rise in blood glucose while PPA failed to show a significant effect on resting blood glucose in either animal. PSD, in normal and GTG mice, caused a hyperglycemia at 2 h after treatment. Reduced stress conditions (nonrepeated orbital sinus blood sampling) or adrenalectomy eliminated the PSD delayed hyperglycemia in normal mice. PSD did not alter immunoreactive insulin levels at 2 h; however, PSD caused significantly higher corticosterone levels in normal and GTG mice at 2 h. PPA, which did not cause hyperglycemia, had no effect on corticosterone levels at 2 h in normal mice.

The glycemic effects of sympathomimetics in stressed mice.

Sympathomimetics are extensively used clinically as decongestants and bronchodilators in cough, cold, and sinus remedies. However, few studies have addressed the glycemic potentials of these drugs. In this study, the glycemic potentials of pseudoephedrine (PSD), ephedrine (EPD), and phenyl-propanolamine (PPA), the three most commonly used sympathomimetics, were evaluated. PSD caused a dose-dependent delayed hyperglycemia. This was attenuated when procedural stress was reduced. EPD and PPA did not increase the hyperglycemia due to procedural stress. EPD and PPA blunted the hyperglycemia in fed mice after a 2 g/kg oral glucose challenge; PSD had no effect. The effects of PPA and EPD on post-challenge glucose levels may be partially explained by increased insulin/glucose ratios at 15 minutes post-challenge. These studies indicate that there are differences in the glycemic effects among the sympathomimetics in stressed mice.

Selected cardiac and metabolic responses to pseudoephedrine with exercise.

Pseudoephedrine hydrochloride was evaluated at two dosage levels in six normal healthy males, at rest and during submaximal exercise. Although there appeared to be a dose-related rise and during submaximal exercise. Although there appeared to be a dose-related rise in resting heart rate, it was not statistically significant. The drug had no effect on the amount of time required to reach 85 per cent maximal predicted heart rates while on the treadmill or on the amount of time required to recover baseline heart rates. Also, there was no drug effect observed on blood pressure at rest, during exercise, or in the recovery period. There was a significant increase in the frequency of sinus arrhythmias after the 120-mg pseudoephedrine dose. There appeared to be no drug effect on postexercise blood glucose and insulin levels.