Abstract: FR-PO357
V1a Receptor-Mediated Kidney Tissue Oxygenation Is Independent of Vasopressin V2 Receptor Blockade
Session Information
- CKD: Mechanisms - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): 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
AVP binds to two subtypes of receptors in the kidney, the V1a and V2 receptors mediating different cellular effects. Selective V2 receptor antagonism induces aquaresis and is an efficacious decongestive approach. We showed that selective V1a receptor inhibition improves kidney oxygenation and kidney function which might be relevant for conditions of increased AVP levels such as chronic kidney disease. We investigated the potential interference of selective V2 antagonism with V1a antagonism on kidney oxygenation.
Methods
The effects of selective V2 antagonism (tolvaptan or satavaptan), selective V1a antagonism (relcovaptan) or a combination of both on renal blood flow (RBF) and tissue oxygenation (pO2) were investigated in isolated perfused rat kidneys (IPK) and in anesthetized Sprague Dawley rats (n=7 per group) via Laser Doppler Flowmetry in settings of increased AVP levels.
Results
Tolvaptan (0.3–100 nM) had no effect on the AVP-mediated (50 nM) reduction of perfusate flow while increasing urine excretion (p=0.07). In vivo, infusion of AVP (50 ng/kg/min i.v.) significantly increased mean arterial pressure (MAP) and reduced both RBF and tissue pO2 (Table 1). Dose-dependent infusion of tolvaptan did not reduce the increased MAP values and did neither restore RBF nor kidney pO2 levels. Similar results were achieved with satavaptan. Combination of V1a antagonism (relcovaptan) with V2 antagonism (tolvaptan) normalized AVP-increased MAP and restored RBF and pO2 back to basal values similar to the individual V1a antagonism (Table 1).
Conclusion
Selective V2 inhibition has no impact on renal oxygenation in settings of increased AVP levels and does not interfere with V1a receptor blockade-mediated beneficial effects on kidney oxygenation. Therefore, addressing the individual vasopressin receptors alone or in combination in cardiorenal diseases is dependent on the presence of congestion and/or kidney hypoxia.
*/**** p<0.05/0.0001 vs. AVP (One-way ANOVA)
#/##/#### p<0.05/0.01/0.0001 vs. AVP (t test)
Funding
- Commercial Support –