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Abstract: PO0647

The Novel Potent and Selective Vasopressin V1a Antagonist BAY2327949 Blocks Arginine Vasopressin-Mediated Decline of Renal Blood Flow and Tissue Oxygenation

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Cernecka, Hana, Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany
  • Droebner, Karoline, Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany
  • Tinel, Hanna, Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany
  • Pook, Eisabeth, Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany
  • Fuerstner, Chantal, Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany
  • Collin, Marie-Pierre Laure, Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany
  • Hein, Peter, Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany
  • Eitner, Frank, Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany
  • Kolkhof, Peter, Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany
Background

Hypoxia is a major contributor to kidney disease progression. Arginine vasopressin (AVP) potently induces renal medullary vasoconstriction via vascular V1 receptors resulting in reduced renal blood flow (RBF). Here we characterized the kidney-protective properties of a recently identified, potent and selective V1a receptor antagonist.

Methods

BAY 2327949 was characterized in Chinese hamster ovary cells expressing recombinant human and rat V1a and V2 receptors. Vasodilatory effects were investigated on isolated A. renalis rings from male Wistar rats (n=10). RBF and intrarenal tissue oxygenation were studied in isolated perfused rat kidneys and in anesthetized rats (n= 5-8 per group) via Laser Doppler Flowmetry.

Results

In vitro receptor profiling showed high potency and selectivity of BAY 2327949 for human V1a receptor (IC50 hV1a: 1.2 nM, IC50 hV2: 170 nM). BAY 2327949 mediated dose-dependent relaxation (IC50= 3.1 nM) of isolated rat A. renalis vessel rings precontracted by AVP. BAY 2327949 improved the AVP-mediated reduction of perfusate and venous flow (figure) without affecting urinary volume. In vivo, infusion of AVP significantly increased mean arterial pressure (CON: 97±1, AVP: 135±12; mean±SD) which was normalized by BAY 2327949 in a dose-dependent manner (90±5; p<0.0001). Infusion of AVP reduced both renal perfusion (CON: 1060±8, AVP: 758±107) and tissue oxygenation (CON: 27±1, AVP: 17±4). BAY 2327949 dose-dependently restored RBF (960±30; p<0.0001) and increased pO2 (25±0.4; p<0.0001).

Conclusion

BAY 2327949 is a novel potent and selective vasopressin V1a receptor antagonist blocking the detrimental effects of elevated vasopressin levels on renal perfusion and oxygenation in rats, suggesting potential benefit for patients with cardiorenal diseases.

Funding

  • Commercial Support