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.