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 (BH(4)) may contribute to endothelial dysfunction. We investigated the effect of L-arginine and BH(4) 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 BH(4) (500 microg/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 BH(4) infusion. EDV was also significantly less reduced at 15 and 30 min of reperfusion following L-arginine and BH(4) 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 BH(4) (P<0.0001), whereas there was no difference in biopterin levels during saline infusion. In conclusion L-arginine and BH(4) 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.
Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. magnus.settergren@karolinska.se
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M
Settergren
F
F
Böhm
R E
RE
Malmström
K M
KM
Channon
J
J
Pernow
D000368:Aged; D001120:Arginine / Q000008:administration & dosage*; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives*; D001783:Blood Flow Velocity; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000503:physiopathology; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D012039:Regional Blood Flow; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage
D002317:Cardiovascular Agents; D014665:Vasodilator Agents; D001708:Biopterins; D001120:Arginine; C003402:sapropterin