Endothelial Dysfunction in Superior Mesenteric Arteries Isolated from Adenine-Induced Renal Failure in Model Rats.

Endothelial dysfunction-a hallmark of chronic kidney disease (CKD)-is one of the major risk factors for cardiovascular diseases (CVD). Imbalances in endothelium-derived relaxing factors (EDRFs) and contracting factors (EDCFs) specific to endothelial dysfunction in CKD are yet to be studied. Therefore, using adenine-treated rats-a CKD rat model-we investigated the responsiveness of superior mesenteric artery (SMA) endothelium to acetylcholine (ACh) stimulation under different experimental conditions. Nine-week-old male Wistar rats were treated daily with adenine (200 and 600 mg/kg body weight) by oral gavage, for 10 d; the two groups were named adenine-200 (200 mg/kg body weight) and adenine-600 (600 mg/kg body weight). The systolic blood pressure (measured 1-, 8-, and 15 d post-treatment) was significantly increased in the adenine-600 group compared with that in the control group; whereas that in the adenine-200 group showed only a slight increase. Moreover, in the adenine-600 group the serum creatinine and blood urea nitrogen (BUN) levels (measured at 18 d post-treatment) were significantly elevated when compared with those in control or adenine-200 groups. The ACh-mediated relaxation was slightly reduced in the adenine-200 group. The ACh- and sodium nitroprusside (SNP)-mediated relaxations were impaired in the adenine-600 group. Although no ACh-mediated contraction was observed in the presence of a nitric oxide (NO) synthase inhibitor, ACh-induced endothelium-derived hyperpolarizing factor-mediated relaxation was largely impaired in the adenine-600 mg/kg group. This study revealed that in the SMA of adenine-induced CKD model rats, EDCF signaling remained unaltered while the NO and EDHF signaling were impaired.

Methylglyoxal impairs ATP- and UTP-induced relaxation in the rat carotid arteries.

Although methylglyoxal (MGO), a highly reactive dicarbonyl compound, influences the functioning of the vasculature, modulating its effects on vascular reactivity to various substances remains unclear, especially purinoceptor ligands. Therefore, we sought to investigate the direct effects of MGO on relaxation induced by adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) in isolated rat carotid arteries. When carotid arteries were exposed to MGO (420 µM for 1 h), relaxation induced by acetylcholine or sodium nitroprusside was not affected by MGO. However, ATP- and UTP-induced relaxation was impaired by MGO compared with the control. In both ATP- and UTP-induced relaxation, endothelial denudation, incubation with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine or the selective P2Y purinoceptor 2 (P2Y2) receptor antagonist AR-C118925XX reduced relaxation in both the control and MGO groups, while the differences between the control and MGO groups were eliminated. The cyclooxygenase (COX) inhibitor indomethacin inhibited the differences in ATP/UTP-mediated relaxations between the control and MGO groups. Moreover, N-acetyl-L-cysteine (NAC), an antioxidant, could augment carotid arterial relaxation induced by ATP/UTP in the presence of MGO. MGO increased arachidonic acid-induced contraction, which was suppressed by NAC. Following both ATP/UTP stimulation, MGO increased the release of prostanoids. These results suggest that MGO impaired ATP- and UTP-induced relaxation in carotid arteries, which was caused by suppressed P2Y2 receptor-mediated signaling and reductions in endothelial NO. Moreover, MGO partially contributed to COX-derived vasoconstrictor prostanoids through increased oxidative stress.

[Relationship between gut microbiota-derived substances and vascular function: focus on indoxyl sulfate and trimethylamine-N-oxide].

Emerging evidences suggest that gut microbiota-derived substances play a pivotal role in the regulation of host homeostasis including vascular function. Actually, these substances and/or their metabolites can be presented in circulation and local tissue and their levels are often abnormal in the pathophysiological states. Therefore, to determine the role of them in physiological function is important in human health. On the other hand, vascular dysfunction is a key event in the initiation and progression of systematic complications of cardiovascular, kidney and metabolic diseases including hypertension, dyslipidemia, diabetes, and atherosclerosis. Although abnormalities in endothelial and vascular smooth muscle cells play an important role on vascular dysfunction, emerging evidences has suggested that gut microbiota-derived substances can directly or indirectly affect these cellular functions. The present review will focus on the relationship between vascular function and indoxyl sulfate or trimethylamine-N-oxide (TMAO).