David E. Potter

The influence of propranolol on catecholamine-induced changes in carbohydrate metabolism in the rabbit.

In vitro evidence has indicated that isoproterenol (ISO) is more potent than epinephrine (EPI) in releasing glucose from rabbit liver slices and that propranolol (PROP) is a competitive antagonist of ISO. In contrast, dose-response data from fasted rabbits have shown that EPI is more potent than ISO in increasing plasma glucose levels and in lowering hepatic glycogen levels. Pretreatment with PROP abolished ISO-induced hyperglycemia and changes in liver and muscle glycogen levels whereas only the muscle glycogen depleting effect of EPI was altered significantly. These results suggest that factors other than stimulation of hepatic beta-receptors must be involved in EPI-stimulated depletion of liver glycogen and hyperglycemia in the intact rabbit.

Catecholamine-induced changes in plasma glucose and insulin levels in the unanesthetized rabbit.

Isoproterenol (ISO) produced dose-related increases in plasma immuno-reactive insulin (IRI) levels in unanesthetized rabbits, whereas epinephrine produced no significant changes. Dose rats of ISO or glucose that produced similar peak increases in glucose levels also produced similar increases in plasma IRI, but the responses to ISO occurred later and were of longer duration than the responses to glucose. Propranolol blocked the increase in plasma IRI produced by ISO, but the ISO-induced rise in plasma glucose was antagonized imcompletely. These data provide supporting evidence for the suggestion that the hyperglycemic activity of ISO in vivo is limited by concurrent ISO-induced changes in peripheral IRI levels.

Metabolic responses to isoproterenol and epinephrine in the rabbit: Influence of state of nourishment, alloxan diabetes and pretreatment with propranolol

Abstract Previous reports have shown that isoproterenol (ISO) is less active then epinephrine (EPI) in producing hyperglycemia in rabbits in vivo but ISO in vitro is more active than EPI in releasing glucose from rabbit liver slices. This difference in activities of the catecholamines in vivo was investigated by comparing responses in plasma glucose, lactate and glycerol in fed normal, fasted normal and fed alloxan-diabetic rabbits. Changes in the state of nourishment had more effect on the plasma glucose response to EPI than to ISO. In Contrast, the hyperglycemic response to ISO was augmented by prior chemical destruction of pancreatic β-cells whereas the peak response to EPI was unchanged. Neither the lactate nor the glycerol responses to the catecholamines were modified drastically by changes in the state of nourishment or by lack of endogenous insulin release. Pretreatment with propranolol in fed normal rabbits suppressed the rise in lactate and glycerol induced by both catecholamines, but the rise in glucose produced by EPI was not depressed and the rise produced by ISO was inhibited by only 50 per cent. These results suggest that the hyperglycemic response to EPI is primarily a result of hepatic glycogen breakdown whereas the response to ISO is largely dependent upon gluconeogenic mechanisms. Therefore, catecholamines may not only affect certain metabolic substrate levels by direct actions on liver, muscle and adipose tissue, but they may also influence the responsiveness of the pancreatic islet cells, which, in turn, alters the disposition of key metabolic substrates.

Catecholamine-induced alterations in glucose homeostasis in baboons, dogs, rabbits, and rats: Comparative effects of somatostatin

Abstract A considerable amount of species variation exists in the relative hyperglycemic activities of catecholamines. For example, epinephrine (EPI) is a potent hyperglycemic agent in all mammalian species, whereas isoproterenol (ISO) has strong hyperglycemic activity in dogs, moderate activity in baboons, weak activity in rabbits, and relative inactivity in normal fed rats.1.2 Moreover, in rabbits there are differences between the in vitro glucose mobilizing activities of catecholamines as compared to in vivo effects.3 This suggests that there may be important indirect determinants of hyperglycemic activity that account for the species variation in the relative hyperglycemic activities of catecholamines. Previous work from our laboratory has shown that the hyperglycemic effect of ISO in rats is limited by its stimulating effect on insulin release.4 On the basis of indirect evidence, Sokal and Sarcione5 suggested that the hyperglycemia produced by EPI is mediated through increased glucagon release. Since catecholamines have been shown to release the potent glycogenolytic and gluconeogenic hormone, glucagon,6 it seems appropriate to examine the involvement of glucagon as well as insulin in the production of hyperglycemia by catecholamines in a variety of laboratory animals. We have hypothesized that pancreatic hormone release is an important determinant of catecholamine-induced hyperglycemia, and different patterns of pancreatic hormone release may explain, in part, the differences in the relative hyperglycemic activities of catecholamines that occur within and between species.

Metabolic and cardiovascular effects of carbuterol and metaproterenol

Metabolic and cardiovascular responses to selective beta-adrenergic bronchodilators, carbuterol and metaproterenol, were studied during an asymptomatic period in 8 male subjects with bronchial asthma diagnosed as mile to moderate. On separate days each individual received either placebo, carbuterol 2 mg, carbuterol 4 mg, or metaproterenol 20 mg orally in a double-blind fashion. Subsequently, metabolic and cardiovascular responses were measured periodically for 5 hr. Carbuterol 2 mg was indistinguishable from placebo except for small elevations of glucose at 3 and 4 hr. Carbuterol 4 mg produced significant increases in glucose, insulin, lactate, and free fatty acids as well as in pulse rate and arterial pulse pressure. Metaproterenol produced increases only in plasma glucose and insulin. The majority of patients reported drug-related side effects which were all mild, after taking either carbuterol 4 mg or metaproterenol 20 mg. Fewer subjective side effects were noted with carbuterol 2 mg. These findings indicate that a 2-mg dose of carbuterol can be administered to typical asthmatic subjects without significant subjective or objective side effects. The larger dose (4 mg) may be accompanied by a greater frequency of side effects.

Changes in Plasma Glucose and Insulin Levels Induced by Adrenergic Agents in Normal and Alloxan-Diabetic Rats

Summary Isoproterenol-induced insulin release in fed normal rats and hypergly-cemia in fed alloxan diabetic rats were inhibited by pretreatment with propranolol. Moreover, salbutamol, another /8-adrener-gic stimulant, appears to have some insulin releasing activity in the fed normal rat although its glucose mobilizing activity seems to be preponderant. Epinephrine and nor-epinephrine, on the other hand, have weak or no insulin releasing activity acutely and are more potent hyperglycemic agents than isoproterenol in the fed normal rat. These results suggest that insulin release by isoproterenol and by salbutamol in normal rats can attenuate the hyperglycemic activity of these β-adrenergic receptor agonists. Suppression of insulin release by treatment with alloxan discloses the substantial glucose mobilizing effects of isoproterenol in the rat. The authors are grateful to Dr. Mary A. Root of Eli Lilly and Co. for a generous gift of protamine zinc insulin, Dr. R. O. Davies of Ayerst Laboratories for a generous supply of propranolol (Inderal), and Dr. I. A. A. Tabachnick of The Schering Corporation for a gift of salbutamol.

EFfects of ethanol and 3-mercaptopicolinic acid on isoproterenol and epinephrine-induced changes in glucose homeostasis in normal and alloxan-diabetic rats☆

Abstract The relative contribution of gluconeogenesis to the catecholamine-induced hyperglycemic response in rats remains controversial. In the present study, fasted rats were treated acutely with either ethanol or 3-mercaptopicolinic acid and then challenged later with saline, epinephrine or isoproterenol. Pretreatment with either agent suppressed the hyperglycemic response to isoproterenol more than the response to epinephrine. Isoproterenol-induced changes in blood lactate were augmented by ethanol pretreatment in normal fasted rats. In alloxan-diabetic rats, the augmented hyperglycemic response to isoproterenol was partially suppressed by pretreatment with ethanol or 3-mercaptopicolinic acid. Interestingly, pretreatment of normal, fed rats with ethanol unmasked a hyperglycemic response to isoproterenol which appeared to be the result of inhibition of insulin release. These data suggest that the hyperglycemic response to catecholamines in normal, fasted and alloxan-diabetic rats is due, in part, to stimulation of gluconeogenesis and that the response to isoproterenol in fasted rats is more dependent upon gluconeogenesis than is the response to epinephrine.

Isoproterenol and epinephrine-induced hyperglycemias in rabbits: effects of alloxan treatment and prandial state.

Summary 1. The hyperglycemic effects of epinephrine and isoproterenol were compared in rabbits subjected to changes in prandial state and to treatment with alloxan. 2. Hyperglycemic responses to epinephrine were greater in normal-fed rabbits than in normal-fasted rabbits. Changes in the prandial state produced no alteration in the hyperglycemic response to isoproterenol. 3. Isoproterenol produced greater hyperglycemic responses in alloxan-diabetic, fed rabbits than in normal-fed rabbits, whereas, epinephine was of equal potency in alloxan-diabetic, fed rabbits and normal-fed rabbits. 4. The marked difference in the relative potencies of isoproterenol and epinephrine in elevating blood glucose (EPI > ISO) in normal rabbits and in increasing glucose release from rabbit liver slices (ISO > EPI) may be related, at least in part, to the insulin-releasing activity of isoproterenol and to the suppression of insulin release by epinephrine. The skillful technical assistance of Miss Lois Wilson in these experiments is gratefully acknowledged. The authors also wish to express their appreciation to Dr. Mary A. Root of Eli Lilly and Company for a generous gift of protamine zinc insulin, and to Mrs. Dorothy Austin for her secretarial assistance. This work was supported in part by NIH Grant NS 07700 05.

Suppression of Isoproterenol-Induced Hyperglycemia by Ethanol

Summary Ethanol inhibited markedly the hyperglycemic response to isoproterenol in the fasted rat, whereas the hyperglycemic response to epinephrine was not changed significantly. Since ethanol is a potent inhibitor of gluconeogenesis, these data give support to the suggestion that isoproterenol produces its hyperglycemic effect in the fasted rat by mechanisms involving gluconeogenesis. Furthermore, this work suggests that isoproterenol-induced hyperglycemia in the fasted rat may provide an animal model for testing other inhibitors of gluconeogenesis.

Role of glucagon in the hyperglycemic response to catecholamines in fasted baboons

The hyperglycemic activities of epinephrine (EPI) and isoproterenol (ISO) in baboons correlated with their ability to increase plasma glucagon (IRG) levels relative to insulin (IRI). EPI inhibited IRI release and produced greater increases in plasma glucose and IRG than did ISO. ISO increased plasma IRI levels more than IRG. Infusion of somatostatin blocked IRG release and inhibited hyperglycemic responses to EPI by approximately 50%. These findings indicate that, as in man, IRG release contributes significantly to the hyperglycemic effects of catecholamines in baboons. The baboon thus appears to be a suitable model for predicting effects of drugs on glucose homeostasis in humans.