Abstract
The roles of nitric oxide (NO), endothelium-derived hyperpolarizing factors (EDHF), and calcium-activated K+ (KCa) channels in diabetes-associated endothelial dysfunction of small renal arteries are not clear. The present study investigated acetylcholine (ACh)-induced vasorelaxation of renal arcuate arteries from obese Zucker (OZ) rats at different diabetes durations, and the relative contribution of NO, EDHF, and KCa channels to the endothelial dysfunction. OZ rats of 7 weeks (prediabetic stage), 12 weeks (early diabetic stage), and 20 weeks (late diabetic stage), and time-matched lean control rats, were studied. Segments of arcuate arteries (130 to 180 μm) were isolated, cannulated and pressurized. Vascular endothelial functions were tested using ACh-induced vasodilation. Our experiments demonstrated: (1) ACh-elicited vasodilation was impaired in OZ rats of 20 weeks, but not in rats of 7 and 12 weeks; (2) inhibition of NO or EDHF (contributed by epoxyeicosatrienoic acids [EETs]) production significantly decreased ACh-induced vasodilation in both lean and OZ rats of 20 weeks. The reduction of ACh-induced vasodilation by inhibition of NO or EDHF formation was less in OZ rats, as compared to lean rats; and (3) inhibition of KCa channels markedly reduced ACh-induced vasodilation in lean control rats, but not in OZ rats of 20 weeks. Our observations indicated that endothelium-dependent vasodilation in renal arcuate arteries is impaired in diabetes mellitus; NO and EDHF, mainly EETs, dominate the ACh-induced vasodilation in renal arcuate arteries; the contribution of NO and EETs is impaired in diabetic rats; KCa channels are involved in ACh-induced vasodilation; and the activity of KCa channels is downregulated in diabetes mellitus.
Highlights
Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular complications, which account for most of the morbidity and mortality [1]
The present study investigated the influence of diabetes on the different stages and components of endothelium-dependent vasodilation in the renal arcuate arteries of obese Zucker (OZ) rats in vitro
The major findings are: (1) ACh-elicited vasodilation was impaired in late diabetic OZ rats at 20 weeks, but not in 7 week prediabetic or 12 week early diabetic rats; (2) Both nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHF) mediated the ACh-elicited vasodilation in renal arcuate arteries of late diabetic OZ rats, and their contributions were reduced; and (3) K+ channels (KCa) channels were involved in the ACh-elicited vasodilation and their function was impaired in late diabetic OZ rats
Summary
Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular complications, which account for most of the morbidity and mortality [1]. The roles of NO, EDHF and KCa channels in endothelial dysfunction of renal arcuate arteries evidence demonstrated that impaired endothelium-dependent relaxation existed consistently in both conduit and resistance arteries of diabetes mellitus [2,3,4]. The impaired contribution of NO or EDHF to endothelium-dependent vasodilation was demonstrated in renal arteries of rats with type 2 diabetes [15,16,17,18] These findings raise the possibility that, in renal arterioles of type 2 diabetic rats, endothelial dysfunction results from the compromised function of NO, EDHF, and KCa channels. In the present study, OZ rats at different diabetic stages were used to examine ACh-induced vasorelaxation in renal arcuate arteries, and to investigate the contributions of NO, EDHF, and, KCa channels to endothelial dysfunction at the late stage of this animal model
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