Background: Arginase is an important regulator of nitric oxide production by competing with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in patients with coronary artery disease (CAD) and diabetes mellitus (DM) may thereby be of major importance for the development of endothelial dysfunction and ischemia-reperfusion (IR) injury by reducing the bioavailability of nitric oxide. Accordingly, arginase inhibition reduces infarct size and improves endothelial function by nitric oxide synthase-dependent processes in animal models. Purpose: To investigate if arginase inhibition protects from endothelial dysfunction induced by IR in patients with CAD with and without DM. Methods: Male patients with CAD (n=12) or CAD + DM (n=12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and 20 min after a 20 min period of arm ischemia. The patients were given an intra-arterial infusion of the arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA, 0.1 mg/min) or saline on the two occasions. The infusions were given for 20 min starting 5 min before reperfusion. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Results: IR decreased FMD in patients with CAD from 12.7±1.5% to 7.9±1.2% during saline administration. Nor-NOHA administration prevented the decrease in FMD in the CAD group (11.5±1.0% FMD at reperfusion, P<0.0.5 vs. saline). Baseline endothelium-dependent vasodilatation was significantly lower in the CAD+DM group (8.3±0.6%) than in the CAD group (P<0.05). IR induced a non-significant decrease in FMD in patients with CAD+DM. FMD at reperfusion was higher following nor-NOHA (11.2±1.0%) than following saline (7.2±1.0%) administration in the CAD + DM group (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions in either group.
Conclusions: Inhibition of arginase protects against endothelial dysfunction caused by IR in patients with CAD. Arginase may thereby be a promising therapeutic target in the treatment of IR injury.