Inhibition of Ras-GTPase improves diabetes-induced abnormal vascular reactivity in the rat perfused mesenteric vascular bed.
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.


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.


CONCLUSIONS
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.
Yousif
Mariam H M
MH
Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait. mariam@hsc.kuniv.edu.kw
Benter
Ibrahim F
IF
Abraham
Saju
S
Akhtar
Saghir
S
D000818:Animals; D002217:Carbachol / Q000008:administration & dosage; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006632:Histamine / Q000008:administration & dosage; D006801:Humans; D007545:Isoproterenol / Q000008:administration & dosage; D008638:Mesenteric Arteries / Q000201:enzymology / Q000502:physiology*; D009638:Norepinephrine / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D019332:Endothelin-1; D006632:Histamine; D002217:Carbachol; D020558:GTP Phosphohydrolases; D018631:ras Proteins; D007545:Isoproterenol; D009638:Norepinephrine