Abstract: SA-PO827
Renal Hemodynamic Effects of a sGC Stimulator vs Activator in Conscious Sprague-Dawley and Obese Diabetic ZSF1 Rats
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Griffin, Karen A., Loyola University Medical Center Hines VA Hospital, Maywood, Illinois, United States
- Williamson, Geoffrey A., Illinois Institute of Technology, Chicago, Illinois, United States
- Sethupathi, Perriannan, Loyola University Medical Center, Maywood, Illinois, United States
- Benardeau, Agnes M., Bayer Pharma AG, Wuppertal, Germany
- Bidani, Anil K., Loyola University Med Ctr and Hines VA Hospital, Maywood, Illinois, United States
Background
Endothelial dysfunction and/or NO loss accelerate the progression of diabetic and non-diabetic chronic kidney disease (CKD). Therefore, soluble guanylate cyclase (sGC) stimulators and activators are being developed as potential novel therapeutic interventions in CKD. Stimulators sensitize sGC to low levels of bioavailable NO in the presence of reduced (ferrous) prosthetic heme, while sGC activators preferentially activate sGC when it is in an oxidized or heme free state. But their comparative renal hemodynamic effects have not been examined in conscious rat models.
Methods
Conscious chronically instrumented conscious Sprague-Dawley rats (body weight ~300g) and obese diabetic ZSF1 rats (body wt ~500g) underwent repeated simultaneous 1-2 hr BP (radiotelemetry) and RBF (Transonic) recordings over 3 wks (2-4 x wk) while they were sequentially receiving: vehicle only by gavage (5 ml/kg), a low and a high dose of either the sGC activator (BAY-543) or the stimulator (BAY-747) (3-4 days/wk with a ~3 day washout period). Effects on mean arterial pressure (MAP), RBF, renal vascular resistance (RVR) and the autoregulatory (AR) ability to buffer spontaneous BP fluctuations were assessed using a methodology recently developed in our lab.
Results
Table (mean + SEM)
While both the sGC stimulator and the sGC activator in the dosages used had similar BP effects in both SD and ZSF1 rats, the sGC activator tended to produce greater renal vasodilation with both doses in both strains but which was significant only in the ZSF1 rats. Despite the renal vasodilation, AR buffering of spontaneous BP fluctuations was not impaired by either agent in either strain.
Conclusion
The significantly greater renal vasodilatory effects of sGC activator in a renal disease model, the ZSF1 rat, may have relevance when considering therapy with sGC modulators in CKD states.
| SPRAGUE DAWLEY | ZSF-1 | ||||||
| MAP (mmHg) | RBF (ml/min) | RVR (mmHg/ml.min) | MAP (mmHg) | RBF (ml/min) | RVR (mmHg/ml.min) | ||
| sGC Stimulator (BAY-747) | |||||||
| Vehicle | 103.0 ± 3.2 | 8.5 ± 0.6 | 12.9 ± 1.4 | 127.8 ± 3.1 | 8.8 ± 0.7 | 15.1 ± 0.8 | |
| 0.3 mg/kg (Δ%) | −1.8 ± 2.1 | +5.8 ± 8.2 | −3.3 ± 7.0 | −3.6 ± 2.4 | +0.6 ± 5.7 | −0.9 ± 4.9 | |
| 1.0 mg/kg (Δ%) | −7.3 ± 1.5* | +12.3 ± 1.1 | −13.7 ± 8.4* | −6.7 ± 1.7 | +10.2 ± 6.2 | −12.4 ± 5.9 | |
| sGC Activator (BAY-543) | |||||||
| Vehicle | 105.2 ± 3.5 | 7.9 ± 0.3 | 13.7 ± 0.9 | 129.4 ± 2.2 | 9.2 ± 0.8 | 15.2 ± 1.5 | |
| 3 mg/kg (Δ%) | −1.7 ± 2.2 | +11.9 ± 3.4 | −11 ± 2.9 | −5.4 ± 1.8 | +19.2 ± 2.9# | −20.6 ± 2.7# | |
| 10 mg/kg (Δ%) | −9.0 ± 1.9* | +25.4 ± 9.2 | −24.9 ± 6.4* | −12.4 ± 1.7*# | +45.7 ± 7.2*# | -38.9 ± 3.0*# | |
*p<0.05 maximum vs. lower dose; # 0.05 maximum vs. BAY-747 (n=9-11/group)
Funding
- Commercial Support – Bayer Pharma AG