L-Arginine and tetrahydrobiopterin protects against ischemia/reperfusion-induced endothelial dysfunction in patients with type 2 diabetes mellitus and coronary artery disease

Diminished levels of L-arginine and endothelial nitric oxide synthase (eNOS) uncoupling through deficiency of tetrahydrobiopterin (BH4) May Contribute to endothelial dysfunction. We investigated the effect of L-arginine and BH4 administration on ischemia-reperfusion (I/R)-induced endothelial dysfunction in patients with type 2 diabetes and Coronary artery disease (CAD). Forearm blood flow was measured by venous occlusion plethysmography in 12 patients with type 2 diabetes or impaired glucose tolerance and CAD. Forearm ischemia was induced for 20 min, followed by 60 min of reperfusion. The patients received a 15 min intra-brachial infusion Of L-arginine (20 mg/min) and BH4 (500 mu g/min) or 0.9% saline starting at 15 min of ischemia on two separate study occasions. Compared with pre-ischemia the endothelium-dependent vasodilatation (EDV) induced by acetylcholine was significantly reduced at 15 and 30 min of reperfusion when saline was infused (P<0.001), but not following L-arginine and BH4 infusion. EDV was also significantly less reduced at 15 and 30 min of reperfusion following L-arginine and BH4 infusion, Compared to saline infusion (P<0.02). Endothelium-independent vasodilatation (EIDV) induced by nitroprusside Was unaffected by I/R. Venous total biopterin levels in the infused arm increased from 37 +/- 7 at baseline to 6644 +/- 1240 nmol/l during infusion Of L-arginine and BH4 (P<0.0001), whereas there was no difference in biopterin levels during saline infusion. In Conclusion L-arginine and BH4 supplementation reduces I/R-induced endothelial dysfunction, a finding which may represent a novel treatment Strategy to limit I/R injury in patients with type 2 diabetes and CAD. (C) 2008 Elsevier Ireland Ltd. All rights reserved.