The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the α1-adrenoceptor

SUL-compounds are protectants from cold-induced ischemia and mitochondria! dysfunction. We discovered that adding SUL-121 to renal grafts during warm machine reperfusion elicits a rapid improvement in perfusion parameters. Therefore, we investigate the molecular mechanisms of action in porcine intrarenal arteries (PIRA). Porcine kidneys were stored on ice overnight and perfusion parameters were recorded during treatment with SUL-compounds. Agonist-induced vasoconstriction was measured in isolated PIRA after pre-incubation with SUL-compounds. Receptor binding and calcium transients were assessed in alpha(1)-adrenoceptor (alpha(1)-AR) transgenic CHO cells. Molecular docking simulation was performed using Schrodinger software. Renal pressure during warm reperfusion was reduced by SUL-121 (-11.9 +/- 2.50 mmHg) and its (R)-enantiomer SUL-150 (-13.2 +/- 2.77 mmHg), but not by the (S)-enantiomer SUL-151 (-1.33 +/- 1.26 mmHg). Additionally, SUL-150 improved renal flow (16.21 +/- 1.71 mL/min to 21.94 +/- 1.38 mL/min). SUL-121 and SUL-150 competitively inhibited PIRA contraction responses to phenylephrine, while other 6-chromanols were without effect. SUL-150 similarly inhibited phenylephrine-induced calcium influx and effectively displaced [7-Methoxy-H-3]-prazosin in CHO cells. Docking simulation to the alpha(1)-AR revealed shared binding characteristics between prazosin and SUL-150. SUL-150 is a novel alpha(1)-AR antagonist with the potential to improve renal graft perfusion after hypothermic storage. In combination with previously reported protective effects, SUL150 emerges as a novel protectant in organ transplantation.