Arginase inhibition alleviates hypertension associated with diabetes: effect on endothelial dependent relaxation and NO production.

Increased arginase activity has been reported in a variety of disease conditions characterized by vascular dysfunction. In the present study, the potentially protective effect of arginase inhibition against the hypertension associated with diabetes has been investigated. Diabetes was induced by streptozotocin while arginase inhibitors; citrulline, norvaline and ornithine, were daily administered in the last 6weeks. At the end of study, blood pressure (BP), serum levels of glucose, advanced glycation end products (AGEs) and arginase activity were determined. Concentration response curves for phenylephrine (PE), KCl, and acetylcholine (ACh) were obtained in thoracic aorta rings. ACh-induced NO and reactive oxygen species (ROS) generation in aorta were also studied. Arginase activity was elevated in diabetic animals while significantly inhibited by citrulline, norvaline or ornithine. Diabetes was associated with elevation in systolic and diastolic BP while, arginase inhibition significantly reduced the elevation in diastolic BP. Diabetes increased contractile response of aorta to PE and KCl, decreased relaxation response to ACh while arginase inhibition completely prevented the impaired response to ACh. Diabetes reduces ACh stimulated NO but increased ROS generation while arginase inhibition restores normal NO and ROS generation. In addition, acute incubation with arginase inhibitors improved response to ACh but not PE or KCl in aorta isolated from diabetic animals. Diabetes was associated with a significant increase in serum AGEs while all the used arginase inhibitors normalize it. In conclusion, arginase inhibition alleviates hypertension in diabetes through a mechanism involving prevention of the impairment in endothelial dependent relaxation and NO production.