The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin--induced diabetic rats is restored by 5-methyltetrahydrofolate.
OBJECTIVE
Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiology of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease.


METHODS
Endothelium-dependent and endothelium-independent vasodilator responses were investigated in the renal microcirculation of streptozotocin-induced diabetic rats. We measured renal blood flow changes with an electromagnetic flow probe. In addition, the responses of the different segments of the renal microcirculation were evaluated with videomicroscopy using the hydronephrotic kidney technique. Because endothelial cells release different relaxing factors (nitric oxide, prostacyclin and an unidentified endothelium-derived hyperpolarizing factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor L-NG-nitroarginine methylester HCI (L-NAME) and the cyclooxygenase inhibitor indomethacin. We evaluated with the effect of 5-methyltetrahydrofolate, the active form of folate, on the responses.


RESULTS
The L-NAME- and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with control rats, suggesting impaired endothelium-derived hyperpolarizing factor-mediated vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-i um-1,2-diolate (DETA-NONOate) and to the K+-channel opener pinacidil were similar in diabetics and controls, indicating intact endothelium-independent vasodilator mechanisms. The contribution of endothelium-derived hyperpolarizing factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabetic rats, the response to acetylcholine was increasingly impared as vessel size decreased. Defective vasodilation in diabetic kidneys was rapidly normalized by 5-methyltetrahydrofolate. CONCLUSION-INTERPRETATION: Endothelium-derived hyperpolarizing factor-mediated vasodilation is impaired in the renal microcirculation of diabetic rats, in particular in the smallest arteries. Treatment with folate restores the impaired endothelial function in diabetes.
De Vriese
A S
AS
The Renal Unit, Ghent University, Belgium.
Van de Voorde
J
J
Blom
H J
HJ
Vanhoutte
P M
PM
Verbeke
M
M
Lameire
N H
NH
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D019270:Fructosamine / Q000097:blood; D006869:Hydronephrosis / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply*; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D018715:Microscopy, Video; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012077:Renal Artery / Q000187:drug effects / Q000503:physiopathology; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology*; D013763:Tetrahydrofolates / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D001685:Biological Factors; D015415:Biomarkers; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D013763:Tetrahydrofolates; C067410:endothelium-dependent hyperpolarization factor; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D019270:Fructosamine; D000109:Acetylcholine; C005984:5-methyltetrahydrofolate; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin