Insulinomimetics and the vascular endothelin system
Date
2000-01-01
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Degree Level
Doctoral
Abstract
Insulin promotes vasodilatory, vasoconstrictor and atherogenic influences on vascular smooth muscle. Endothelin-1 (ET-1) is a potent, endothelium derived vasoconstrictor/mitogenic peptide whose production is stimulated by insulin both 'in vitro' and 'in vivo'. Consequently, ET-1 has been hypothesized to contribute to insulin evoked vasculopathy. The present study first characterized the effect of insulin and the insulinomimetic agent, vanadate, on ET receptor expression and action in rat aortic smooth muscle cells. Radioligand binding studies confirmed that insulin pretreatment selectively upregulated ETA receptor expression in a concentration and time dependent manner, whereas vanadate upregulated both ETA and ETB. Upregulated ET receptors were coupled to increased [Ca 2+]i responses to ET agonists. Upregulation by both compounds occurred at the mRNA level and required tyrosine kinase activation, active transcription, and new protein synthesis. In order to determine the ' in vivo' relevance of these effects, both insulin deficient diabetic and non-diabetic rats were treated with insulin and vanadate for 2-weeks. Strikingly, the diabetic state 'per se' was associated with both attenuated ET-1 plasma levels and exaggerated 'ex vivo' aortic vasoconstrictor responses to ET-1. Two weeks of treatment with either insulin or vanadate did not further increase ET-1 evoked vasoconstriction as expected based on our cellular data, but in fact restored altered ET-1 release and action to normal in the diabetic rats. It is concluded that while insulin and vanadate might increase ET receptor expression and subsequent adverse vascular responses to ET-1, their profound beneficial effects on metabolic function and the resulting beneficial vascular actions clearly minimize the significance of these actions.
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Degree
Doctor of Philosophy (Ph.D.)
Department
Pharmacology
Program
Pharmacology