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Abstract: FR-PO101

Selective Vasopressin V1a Receptor Antagonism Improves Renal Oxygenation and Perfusion in AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Cernecka, Hana, Bayer AG, Wuppertal, Germany
  • Droebner, Karoline, Bayer AG, Wuppertal, Germany
  • Mondritzki, Thomas, Bayer AG, Wuppertal, Germany
  • Collin, Marie-Pierre Laure, Bayer AG, Wuppertal, Germany
  • Eitner, Frank, Bayer AG, Wuppertal, Germany
  • Kolkhof, Peter, Bayer AG, Wuppertal, Germany
Background

Vasopressin (AVP) is a neurohormone with a well understood role in urinary volume control via activation of V2 receptors expressed in the collecting duct. The function of renal V1a receptors, which are broadly expressed on vascular smooth muscle cells throughout the medullary vasa recta, in mesangial as well as in macula densa cells, is less well understood. Since reduced blood supply and tissue hypoxia are frequent findings in kidney diseases, we aimed to investigate the potential benefit of selective V1a antagonism (using relcovaptan, SR 49059) in rat models of acute kidney injury (AKI).

Methods

The effects of relcovaptan on renal blood flow (RBF) and tissue oxygenation were investigated in isolated perfused rat kidneys as well as in anesthetized rats (n=7 per group) via Laser Doppler Flowmetry in settings of increased AVP levels induced by either infusion of AVP or renal ischemia/reperfusion injury (I/RI).

Results

Relcovaptan (0.3–300 nM; p<0.001) significantly improved the AVP-mediated (50 nM) reduction of perfusate flow in concentration-dependent manner while having no effect on urine excretion. In vivo, infusion of AVP (50 ng/kg/min i.v.) significantly increased mean arterial pressure (137±3; mean±SEM) which was normalized by relcovaptan in a dose-dependent manner (108±3; p<0.01). Infusion of AVP reduced both renal perfusion and tissue oxygenation (pO2; 7.5±4). Relcovaptan dose-dependently restored renal perfusion and significantly increased pO2 (30.7±6.4; p<0.01). Systemic hemodynamic parameters remained stable under I/RI conditions and concomitant infusion of relcovaptan. Fifteen minutes of ischemia resulted in decreased levels of both RBF and pO2 after reperfusion in comparison with basal levels. In contrast, selective V1 a receptor antagonism significantly improved pO2.

Conclusion

Selective V1a inhibition exerts beneficial effects on renal oxygenation under different pathological settings and might be a promising therapeutic approach to improve kidney hypoxia and subsequently kidney function in conditions of increased AVP levels, such as AKI and CKD.

Funding

  • Commercial Support