Restoration of vascular endothelial function in diabetes.
Nitric oxide (NO) is believed to mediate the phenomenon known as endothelium-dependent relaxation (EDR). NO synthase produces NO from its precursor, arginine (ARG). We have previously demonstrated impaired EDR in diabetic blood vessels. In this study, we investigated a possible mechanism for defective EDR in experimental diabetes and whether pancreatic islet transplantation could reverse established endothelial dysfunction. Streptozotocin-induced diabetic rats were maintained for 8 or 12 weeks. NO-mediated EDR was assessed in isolated thoracic rings ex vivo. A group of untreated diabetic rats received syngeneic islet transplantation at 8 weeks of diabetes and were tested for EDR after 4 weeks of euglycemia. EDR to acetylcholine was impaired in untreated diabetic rings. Endothelium-independent relaxation to nitroglycerin was unaltered. In vitro incubation of diabetic rings with 3 mM L-ARG (but not D-ARG) improved EDR to acetylcholine in rings from 8-week but not 12-week diabetic rats. L-ARG did not alter EDR in control rings nor relaxation to nitroglycerin in control or diabetic rings. Islet transplantation at 8 weeks of diabetes normalized blood glucose, plasma arginine and total glycosylated hemoglobin while restoring normal EDR. In conclusion, a defect in substrate/supply for NO synthesis is acutely reversed by ARG supplementation at early but not at later stages of diabetes. Also, preemptive surgical intervention with islet transplantation prior to the ARG-insensitive phase is an effective strategy to reverse established endothelial dysfunction in diabetes mellitus.
Pieper
G M
GM
Department of Transplant Surgery, Medical College of Wisconsin Froedtert Memorial Hospital, Milwaukee 53226, USA.
Jordan
M
M
Adams
M B
MB
Roza
A M
AM
D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000503:physiopathology* / Q000601:surgery; D004730:Endothelium, Vascular / Q000503:physiopathology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D014664:Vasodilation / Q000502:physiology*
D001786:Blood Glucose; D009569:Nitric Oxide; D001120:Arginine