The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin-induced diabetic rats is restored by 5-methyltetrahydrofolate
As. De Vriese et al., The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin-induced diabetic rats is restored by 5-methyltetrahydrofolate, DIABETOLOG, 43(9), 2000, pp. 1116-1125
Aims/hypothesis. Endothelial dysfunction contributes to the development of
diabetic vascular complications. A better understanding of the pathophysiol
ogy of endothelial dysfunction in diabetes could lead to new approaches to
prevent microvascular disease.
Methods. Endothelium-dependent and endothelium-independent vasodilator resp
onses were investigated in the renal microcirculation of streptozotocin-ind
uced diabetic rats. We measured renal blood flow changes with an electromag
netic flow probe. In addition, the responses of the different segments of t
he renal microcirculation were evaluated with videomicroscopy using the hyd
ronephrotic kidney technique. Because endothelial cells release different r
elaxing 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-ni
troarginine methylester HCI (L-NAME) and the cyclooxygenase inhibitor indom
ethacin, We evaluated with the effect of 5-methyltetrahydrofolate, the acti
ve 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 cont
rol rats, suggesting impaired endothelium-derived hyperpolarizing factor-me
dieted vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(am
inoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate (DETA-NONOate)
and to the K+-channel opener pinacidil were similar in diabetics and contro
ls, 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 diabet
ic rats, the response to acetylcholine was increasingly impared as vessel s
ize decreased. Defective vasodilation in diabetic kidneys was rapidly norma
lized by 5-methyltetrahydrofolate.
Conclusion-interpretation. Endothelium-derived hyperpolarizing factor-media
ted vasodilation is impaired in the renal microcirculation of diabetic rats
, in particular in the smallest arteries. Treatment with folate restores th
e impaired endothelial function in diabetes.