title: Lack of nitric oxide mediation of flow-dependent arteriolar dilation in type I diabetes is restored by sepiapterin.
abstract: The mechanisms leading to microangiopathy in diabetes mellitus have still not been clearly elucidated. We hypothesized that type I diabetes mellitus affects the endothelium and alters flow-dependent dilation of arterioles, an important mechanism involved in local regulation of blood flow. Isolated, pressurized gracilis muscle arterioles (inside diameter approximately 150 microm at 80 mm Hg) from rats with streptozotocin (STZ)-induced diabetes mellitus exhibited reduced dilations induced by increases in perfusate flow compared to those of normal rats (plasma glucose: 25.7 +/- 0.7 vs. 6.4 +/- 0.5 mmol/l; maximum increase in diameter: 15 +/- 4 vs. 31+/- 3 microm, p < 0.05). In control arterioles, both nitric oxide (NO) and prostaglandins mediated the flow-dependent dilation, whereas flow-induced dilations of diabetic arterioles were unaffected by N(omega)-nitro-L-arginine methyl ester (L-NAME) and were abolished by indomethacin. Sepiapterin - precursor of the endothelial NO synthase (eNOS) cofactor tetrahydrobiopterin (BH(4)) - restored the L-NAME-sensitive portion of flow-dependent dilations of diabetic arterioles. Furthermore, depletion of BH(4) by 2,4-diamino-6-hydroxypyrimidine (DAHP) in control arterioles also resulted in reduced flow-dependent dilations, which were restored by intraluminal sepiapterin [but not with superoxide dismutase (SOD) plus catalase (CAT) (SOD+CAT)] and then could be inhibited by L-NAME. Dilations induced by the NO donor sodium nitroprusside (SNP) were unaffected by L-NAME in diabetes mellitus arterioles or when eNOS was activated by intraluminal flow in DAHP-treated arterioles (with or without SOD+CAT). In contrast, pyrogallol (known to produce reactive oxygen species) substantially reduced acetylcholine- and SNP-induced dilation in a SOD+CAT-reversible manner. Collectively, these findings suggest that in diabetic arterioles, due to the reduced bioavailability of BH(4), the synthesis of NO by eNOS is limited, resulting in a reduced flow-induced dilation, a mechanism that may also be responsible for the development of diabetic microangiopathy and exacerbation of other vascular diseases.
authors.affiliation: Department of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
authors.forename: Akos
authors.initials: A
authors.lastname: Koller
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000503:physiopathology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D001783:Blood Flow Velocity; D002374:Catalase / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007042:Hypoxanthines / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D011621:Pteridines / Q000494:pharmacology*; D011622:Pterins; D011748:Pyrogallol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D020030:Nitric Oxide Donors; D011621:Pteridines; D011622:Pterins; D017382:Reactive Oxygen Species; D011748:Pyrogallol; D013481:Superoxides; D009599:Nitroprusside; D001708:Biopterins; D009569:Nitric Oxide; C016727:sepiapterin; D002374:Catalase; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C017202:2,4-diaminohypoxanthine; C003402:sapropterin; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester