Kidney Week

Abstract: FR-PO854

The (R)-Enantiomer of the 6-Chromanol Derivate SUL-121 Counteracts Renal Vasoconstriction by Antagonism of the Α1-Adrenoceptor

Session Information

• Transplantation: Basic
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

• 1801 Transplantation: Basic

Authors

• Nakladal, Dalibor, Department of Clinical Pharmacology, University of Groningen / University Medical Center Groningen, Groningen, Netherlands

Dalibor Nakladal,

• Buikema, Hendrik, Department of Clinical Pharmacology, University of Groningen / University Medical Center Groningen, Groningen, Netherlands

Hendrik Buikema,

• Reyes romero, Atilio, University of Groningen, Groningen, Netherlands

Atilio Reyes romero,

• Krenning, Guido, University Medical Center Groningen/ University of Groningen, Groningen, Netherlands

Guido Krenning,

• Henning, Robert H., Department of Clinical Pharmacology, University of Groningen / University Medical Center Groningen, Groningen, Netherlands

Robert H. Henning,

• Deelman, Leo E., Department of Clinical Pharmacology, University of Groningen / University Medical Center Groningen, Groningen, Netherlands

Leo E. Deelman,

Background

In kidney transplantation, impaired graft perfusion associates with decreased graft survival. Disturbed adrenergic signal transduction during rewarming is an important factor limiting renal perfusion. Recently, we developed a class of 6-chromanol based SUL-compounds which maintain mitochondrial function and limit reactive oxygen species (ROS) during cooling and metabolic stress. Here, we investigate the effects of SUL-121 on vascular function of porcine kidneys.

Methods

Porcine kidneys were collected at a local slaughterhouse and immediately flushed with UW with heparin, placed on ice and transported to the laboratory. The effects of SUL-121 and its enantiomers (R)-SUL-150 and (S)-SUL-151 on renal perfusion pressure was assessed in an isolated kidney perfusion system. In addition, rings from isolated intrarenal arteries were used to measure constriction responses to various agonists after pre-incubation with SUL-compounds. Receptor binding and intracellular calcium transients were assessed in α₁ adrenoceptor transgenic CHO cells. Molecular docking simulation was performed in an α₁ adrenoceptor flexible homology model using Induced Fit software.

Results

Addition of SUL-121, SUL-150 but not SUL-151 caused a decrease (-11±1, -13±2 and -1±1 mmHg, respectively) in renal perfusion pressure. Pre-incubation with SUL-121 and SUL-150 competitively inhibited contraction responses to the α₁ adrenoceptor agonist phenylephrine (pA₂ 5.37±0.03). SUL-151, other 6-chromanols and their metabolites were without effect. Contraction responses to histamine and U46619 were not influenced by SUL-150. Phenylephrine-induced calcium signalling was similarly inhibited by SUL-150 in transgenic CHO cells (pA₂ 5.31±0.03). SUL-150 effectively displaced radiolabelled prazosin in a competitive binding assay. Simulation of molecular docking demonstrated shared binding characteristics of SUL-150 and prazosin.

Conclusion

SUL-150, the (R)-enantiomer of SUL-121, is an antagonist of the α₁ adrenoceptor with ligand-receptor interactions similar to prazosin. Considering the improvement of renal perfusion through adrenergic antagonism in addition to previously reported beneficial effect on mitochondrial function and ROS production, we propose SUL-150 as a novel and unique protectant in kidney transplantation.

Funding

• Commercial Support –