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The alterations of glycogen phosphorylase in diabetic rats and the effects of vanadyl sulphate treatment

University of British Columbia

A supersensitivity to isoproterenol (ISO, 5x10 -9 M)-induced phosphorylase activation in hearts and a decrease in phosphorylase activity in liver from diabetic rats have been previously reported. The nature of this supersensitivity has been investigated in the present study. The effects of treatment with the insulin-like agent vanadyl sulphate (VOSO4) on both diabetes-induced alterations of phosphorylase in heart and liver were also investigated. No difference in the activity ratio (ratio=pH 6.2 activity/pH 8.2 activity) of phosphorylase kinase was observed between diabetic and control hearts under basal conditions. Similar to the profile of phosphorylase alterations in diabetic heart, the activation of phosphorylase kinase in response to ISO-stimulation was significantly increased in diabetic hearts compared to control hearts, suggesting that the alteration of cardiac phosphorylase kinase in the diabetic condition may be partially responsible for the supersensitivity of phosphorylase activation. The cyclic AMP-dependent protein kinase (PKA) cascade is one of the factors that are responsible for the regulation of phosphorylase kinase, which in turn activates phosphorylase by phosphorylation. However, a similar corresponding alteration in ISO-induced elevation of cAMP levels was not observed in diabetic hearts. On the contrary, the increase in cAMP levels in diabetic hearts was significantly lower than that in control rats. This observation strongly challenges the possibility that the supersensitivity is due to an up regulation of the cAMP-PKA cascade. In addition to PKA, phosphorylase kinase is also regulated by calcium. When diabetic hearts were perfused with the calcium channel blocker verapamil (85x10 M) prior to ISO stimulation, we demonstrated that the supersensitivity of phosphorylase activation was abolished. Verapamil also prevented elevation of the cAMP level and activation of phosphorylase kinase by ISO in both control and diabetic hearts. Calcium overload and impaired calcium transport in diabetic heart have been previously reported. This, together with our results suggests that the supersensitivity may be due to diabetes-induced abnormalities in calcium homeostasis in rat hearts. As calcium is also a regulator of phosphorylase kinase, the abnormalities of phosphorylase kinase observed in diabetic hearts are more likely due to altered calcium homeostasis in the hearts, rather than the up-regulation of the cAMP-PKA cascade. As an insulin-like agent, vanadyl sulphate has been shown to have euglycemic effects and to improve cardiac performance of chronically diabetic animals. It has also been demonstrated that vanadium compounds have direct effects on the enzymes of glycogen metabolism. In this study, the supersensitivity of cardiac piosphorylase activation to ISO in diabetic rats was completely abolished by treatment with VOSO4 given in drinking water for five weeks. The treatment also abolished the impairment in the ISO-induced cAMP elevation in diabetic heart. In diabetic livers, a partial restoration of the decreased hepatic phosphorylase activity was achieved by vanadyl sulphate treatment for five weeks, while a complete restoration of hepatic phosphorylase activity was achieved after five months treatment. The present study has thus provided further information toward the understanding of the mechanism(s) involved in the supersensitivity of phosphorylase activation by catecholamines in diabetic rat heart. It has also demonstrated the beneficial effects of vanadyl sulphate treatment on the enzymes responsible for glycogen metabolism.

Thesis/Dissertation

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2008-12-17

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http://hdl.handle.net/2429/3021

Pharmaceutical Sciences

University of British Columbia

UBCV

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