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Direct Impairment of the Endothelial Function by Acute Indoxyl Sulfate through Declined Nitric Oxide and Not Endothelium-Derived Hyperpolarizing Factor or Vasodilator Prostaglandins in the Rat Superior Mesenteric Artery.

Abstract：

:Upon stimulation, endothelial cells release various factors to regulate the vascular tone. In particular, vasorelaxing factors, called endothelium-derived relaxing factors (EDRFs), are altered in the production and/or release, as well as their signaling every vessel and under pathophysiological states, including cardiovascular, kidney, and metabolic diseases. Although indoxyl sulfate is known as a protein-bound uremic toxin and circulating levels are elevated in the impaired kidney functions, direct impact on the vascular function, especially EDRF's signaling, remains unclear. In this study, we hypothesize that acute exposure to indoxyl sulfate could alter vascular relaxation in the rat superior mesenteric artery. Accordingly, we measured acetylcholine (ACh)-induced endothelium-dependent relaxation in the absence and presence of several inhibitors to divide into each EDRF, including nitric oxide (NO), vasodilator prostaglandins (PGs), and endothelium-derived hyperpolarizing factor (EDHF). Indoxyl sulfate reduced the sensitivity to ACh but not sodium nitroprusside. Under cyclooxygenase (COX) inhibition or inhibitions of COX plus source of EDHF, such as small (SKCa)- and intermediate (IKCa)-conductance calcium-activated K+ channels, the decreased sensitivity to ACh in indoxyl sulfate exposed vessel was still preserved. However, under inhibition of NO synthase (NOS) or inhibitions of NOS and COX, the difference of sensitivity to ACh between vehicle and indoxyl sulfate was eliminated. These findings indicated that acute exposure of indoxyl sulfate in the rat superior mesenteric artery specifically explicitly impaired NO signaling but not EDHF or vasodilator PGs.

journal_name

Biol Pharm Bull

journal_title

Biological & pharmaceutical bulletin

authors

Matsumoto T,Takayanagi K,Kojima M,Katome T,Taguchi K,Kobayashi T

doi

10.1248/bpb.b19-00177

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

1236-1242

issue

eissn

0918-6158

issn

1347-5215

journal_volume

pub_type

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Direct Impairment of the Endothelial Function by Acute Indoxyl Sulfate through Declined Nitric Oxide and Not Endothelium-Derived Hyperpolarizing Factor or Vasodilator Prostaglandins in the Rat Superior Mesenteric Artery.