Indoxyl sulfate decreases uridine adenosine tetraphosphate-induced contraction in rat renal artery.

The protein-bound uremic toxin indoxyl sulfate has negative effects on a variety of physiological activities including vascular function. Uridine adenosine tetraphosphate (Up4A), a new dinucleotide molecule affects vascular function including induction of vasocontraction, and aberrant responsiveness to Up4A is evident in arteries from disorders such as hypertension and diabetes. The link between indoxyl sulfate and the Up4A-mediated response is, however, unknown. We used Wistar rat's renal arteries to see if indoxyl sulfate will affect Up4A-mediated vascular contraction. In renal arteries of indoxyl sulfate, the contractile response generated by Up4A was dramatically reduced compared to the non-treated control group. Indoxyl sulfate increased endothelin-1-induced contraction but had no effect on phenylephrine, thromboxane analog, or isotonic K+-induced renal arterial contractions. UTP, ATP, UDP, and ADP-produced contractions were reduced by indoxyl sulfate. CH223191, an aryl hydrocarbon receptor (AhR) antagonist, did not reverse Up4A, and UTP contraction decreases caused by indoxyl sulfate. The ectonucleotidase inhibitor ARL67156 prevents indoxyl sulfate from reducing Up4A- and UTP-mediated contractions. In conclusion, we discovered for the first time that indoxyl sulfate inhibits Up4A-mediated contraction in the renal artery, possibly through activating ectonucleotidase but not AhR. Indoxyl sulfate is thought to play a function in the pathophysiology of purinergic signaling.

[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).