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 (UpA), a new dinucleotide molecule affects vascular function including induction of vasocontraction, and aberrant responsiveness to UpA is evident in arteries from disorders such as hypertension and diabetes. The link between indoxyl sulfate and the UpA-mediated response is, however, unknown. We used Wistar rat's renal arteries to see if indoxyl sulfate will affect UpA-mediated vascular contraction. In renal arteries of indoxyl sulfate, the contractile response generated by UpA 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 UpA, and UTP contraction decreases caused by indoxyl sulfate. The ectonucleotidase inhibitor ARL67156 prevents indoxyl sulfate from reducing UpA- and UTP-mediated contractions. In conclusion, we discovered for the first time that indoxyl sulfate inhibits UpA-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.