THE GLYCEMIC POTENTIALS OF NONCATECHOL SYMPATHOMIMETICS IN SELECTED IN VIVO AND IN VITRO MODEL SYSTEMS
Abstract
The influence of noncatechol sympathomimetics (NCSPM) on glucose metabolism in in vivo and in vitro systems was examined. Ephedrine (EPD) and phenylpropanolamine (PPA) lowered post-challenge glucose levels in fed mice following an oral glucose load of 2 g/kg. Ephedrine, but not PPA, also produced this effect in insulin-resistant goldthioglucose mice. The possibility of an alternative mechanism for the glycemic effects of EPD was examined in an in vitro system. Pretreatment of isolated rat hepatocytes with EPD produced a significant reduction in the dose-response curve for epinephrine(EPI)-induced glucose production. This was consistent with the hypothesis that the glucose-lowering effect of EPD may be due to a blocking of EPI-sensitive receptors responsible for activating liver glycogenolysis. Attempts to increase hepatocyte sensitivity to NCSPM included an investigation into the permissive effects of glucocorticoids on sympathomimetic-stimulated hepatic glucose production. Isolated rat hepatocytes incubated with a combination of cortisol/EPI produced a 38% greater increase in glucose production over hepatocytes incubated with EPI alone. Cortisol alone was also found to produce a significant rise in hepatic glucose output. The enhanced spm effects of glucocorticoids were also demonstrated in hepatocytes from rats pretreated with dexamethasone (DEX). Epinephrine and phenylephrine enhanced glucose production in hepatocytes from DEX-pretreated rats when compared to saline-pretreated rat hepatocytes. Hepatocytes from both normal and DEX-pretreated rats were used to investigate the glycemic potentials of NCSPM. There was little or no effect produced by EPD, PPA or pseudoephedrine (PSD) in nontreated rat hepatocytes. Glucose production was markedly enhanced in hepatocytes from the DEX-pretreated rats. A final study was conducted to further evaluate the direct adrenergic activity of NCSPM in a system more sensitive to (beta)-adrenoreceptor mediation of liver glycogenolysis. Guinea pig hepatocytes were used as the experimental model. A dose-response evaluation of the NCSPM in this model revealed no effect on glucose production by PSD and PPA. A weak dose-related stimulation of glucose production was observed for EPD at concentrations from 10('-5) to 10('-2)M. This suggests a weak direct (beta)-activity for EPD.
Degree
Ph.D.
Subject Area
Pharmacology
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