The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the α 1 -adrenoceptor.

Autor: Nakladal D; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands.; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 832 32, Bratislava, Slovakia., Buikema H; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands., Romero AR; Department of Drug Design, School of Pharmacy, University of Groningen, Antonius Deusinglaan 1 Postbus 196, 9700 AD, Groningen, The Netherlands., Lambooy SPH; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands., Bouma J; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands., Krenning G; Cardiovascular Regenerative Medicine, Dept. Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.; Sulfateq B.V., Admiraal de Ruyterlaan 5, 9726GN, Groningen, The Netherlands., Vogelaar P; Sulfateq B.V., Admiraal de Ruyterlaan 5, 9726GN, Groningen, The Netherlands., van der Graaf AC; Sulfateq B.V., Admiraal de Ruyterlaan 5, 9726GN, Groningen, The Netherlands., Groves MR; Department of Drug Design, School of Pharmacy, University of Groningen, Antonius Deusinglaan 1 Postbus 196, 9700 AD, Groningen, The Netherlands., Kyselovic J; 5th Department of Internal Medicine, Faculty of Medicine, University Hospital, Commenius University, Bratislava, Slovak Republic., Henning RH; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands., Deelman LE; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands. l.e.deelman@umcg.nl.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Jan 09; Vol. 9 (1), pp. 13. Date of Electronic Publication: 2019 Jan 09.
DOI: 10.1038/s41598-018-36788-0
Abstrakt: SUL-compounds are protectants from cold-induced ischemia and mitochondrial 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 α 1 -adrenoceptor (α 1 -AR) transgenic CHO cells. Molecular docking simulation was performed using Schrödinger 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- 3 H]-prazosin in CHO cells. Docking simulation to the α 1 -AR revealed shared binding characteristics between prazosin and SUL-150. SUL-150 is a novel α 1 -AR antagonist with the potential to improve renal graft perfusion after hypothermic storage. In combination with previously reported protective effects, SUL-150 emerges as a novel protectant in organ transplantation.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje