Arginase inhibition restores in vivo coronary microvascular function in type 2 diabetic rats

Gronros J, Jung C, Lundberg JO, Cerrato R, Ostenson C, Pernow J. Arginase inhibition restores in vivo coronary microvascular function in type 2 diabetic rats. Am J Physiol Heart Circ Physiol 300: H1174-H1181, 2011. First published February 4, 2011; doi:10.1152/ajpheart.00560.2010.-Nitric oxide (NO) is crucial for maintaining normal endothelial function and vascular integrity. Increased arginase activity in diabetes might compete with NO synthase (NOS) for their common substrate arginine, resulting in diminished production of NO. The aim of this study was to evaluate coronary microvascular function in type 2 diabetic Goto-Kakizaki (GK) rats using in vivo coronary flow velocity reserve (CFVR) and the effect of arginase inhibition to restore vascular function. Different groups of GK and Wistar rats were given vehicle, the arginase inhibitor N-omega-hydroxy-nor-L-arginine (nor-NOHA), L-arginine, and the NOS inhibitor N-G-monomethyl -L-arginine (L-NMMA). GK rats had impaired CFVR compared with Wistar rats (1.31 +/- 0.09 vs. 1.87 +/- 0.05, P < 0.001). CFVR was restored by nor-NOHA treatment compared with vehicle in GK rats (1.71 +/- 0.13 vs. 1.23 +/- 0.12, P < 0.05) but remained unchanged in Wistar rats (1.88 +/- 0.10 vs. 1.79 +/- 0.16). The beneficial effect of nor-NOHA in GK rats was abolished after NOS inhibition. CFVR was not affected by arginine compared with vehicle. Arginase II expression was increased in the aorta and myocardium from GK rats compared with Wistar rats. Citrulline-to-ornithine and citrulline-to-arginine ratios measured in plasma increased significantly more in GK rats than in Wistar rats after nor-NOHA treatment, suggesting a shift of arginine utilization from arginase to NOS. In conclusion, coronary artery microvascular function is impaired in the type 2 diabetic GK rat. Treatment with nor-NOHA restores the microvascular function by a mechanism related to increased utilization of arginine by NOS and increased NO availability.