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The role of tyrosine kinase-mediated pathways in diabetes-induced alterations in responsiveness of rat carotid artery

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1 G-protein-coupled receptor signalling, including transactivation of receptor tyrosine kinases (RTKs), has been implicated in vascular pathology. However, the role of specific RTKs in the development of diabetes-induced cardiovascular complications is not known.

2 We investigated the ability of a chronic administration of genistein, a broad-spectrum inhibitor of tyrosine kinases (TKs), AG1478, a specific inhibitor of epidermal growth factor receptor (EGFR) TK activity, and AG825, a specific inhibitor of Erb2, to modulate the altered vasoreactivity of isolated carotid artery ring segments to common vasoconstrictors and vasodilators in streptozotocin (STZ)-induced diabetes.

3 In diabetic carotid artery, the vasoconstrictor responses induced by noradrenaline (NE), endothelin-1 (ET-1), and angiotensin II (Ang II), were significantly increased whereas vasodilator responses to carbachol and histamine were significantly reduced. Inhibition of TKs, EGFR or Erb2 pathway did not affect the body weight or agonist-induced vasoconstrictor and vasodilator responses in the non-diabetic control animals. However, inhibition of TKs by genistein, EGFR TK by AG1478 or Erb2 by AG825 treatment produced a significant normalization of the altered agonist-induced vasoconstrictor responses without affecting blood glucose levels. Treatment with diadzein, an inactive analogue of genistein, did not affect the vasoconstrictor and vasodilator responses in the diabetic animals.

4 Treatment with genistein, AG1478 or AG825 resulted in a significant improvement in diabetes-induced impairment in endothelium-dependent relaxation to carbachol and histamine.

5 These data suggest that activation of TK-mediated pathways, including EGFR TK signalling and Erb2 pathway, are involved in the development of diabetic vascular dysfunction in the carotid artery.
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Keywords: AG1478; AG825; carotid artery; diabetes; diadzein; genistein; stroke; tyrosine kinase

Document Type: Research Article

Affiliations: 1: Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait 2: Centre for Genome-based Therapeutics (CGT), Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF, UK

Publication date: 2005-04-01

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