Inhibition of Ras-GTPase Improves Diabetes-Induced Abnormal Vascular Reactivity in the Rat Perfused Mesenteric Vascular Bed

Abstract

Objective: The signalling mechanisms involved in regulating altered vascular reactivity in diabetes are not fully understood. The aim of this study was to investigate the role of Ras-GTPase in the development of abnormal vascular reactivity in diabetes. Materials and Methods: We investigated the ability of chronic administration of FPTIII (1.5 mg/kg), an inhibitor of Ras-GTPase, to modulate the altered vasoreactivity of the rat perfused mesenteric bed to common vasoconstrictors and vasodilators in streptozotocin (STZ)-induced diabetes. Results: The vasoconstrictor responses induced by norepinephrine (NE) and endothelin-1 (ET-1) were significantly increased whereas vasodilator responses to carbachol, histamine and isoprenaline were significantly reduced in the perfused mesenteric bed of the STZ-diabetic rats. Inhibition of Ras-GTPase by chronic administration of FPTIII produced a significant normalization of the altered agonist-induced vasoconstrictor and vasodilator responses without affecting blood glucose levels. Inhibition of Ras-GTPase did not affect the agonist-induced vasoconstrictor and vasodilator responses in the control animals. Conclusion: These data suggest that signal transduction pathways activated by Ras-GTPase are involved in the development of diabetic vascular dysfunction. Potential strategies aimed at modifying actions of signal transduction pathways involving Ras-GTPase may therefore prove to be beneficial in treatment of vascular complications in diabetes. Copyright © 2004 S. Karger AG, Basel.