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Kidney Week

Abstract: FR-PO345

Renal Hemodynamic Effects of Soluble Guanylyl Cyclase Activation vs. ACE Inhibition in a CKD Model in Conscious Rats

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

  • Griffin, Karen A., Loyola University Med Ctr and Hines VA Hospital, Maywood, Illinois, United States
  • Williamson, Geoffrey A., Illinois Institute of Technology, Chicago, Illinois, United States
  • Sethupathi, Perriannan, Loyola University Med Ctr and Hines VA Hospital, Maywood, Illinois, United States
  • Benardeau, Agnes M., Bayer AG, Wuppertal, Germany
  • Schomber, Tibor, Bayer AG, Wuppertal, Germany
  • Eitner, Frank, Bayer AG, Wuppertal, Germany
  • Bidani, Anil K., Loyola University Med Ctr and Hines VA Hospital, Maywood, Illinois, United States
Background

BP control using renin-angiotensin system (RAS) blockade is the current standard of care for CKD. However, outcomes remain suboptimal in part because adequate BP reductions are difficult to achieve in the volume expanded CKD states with RAS blockade even with additional antihypertensives. Given that endothelial dysfunction and/or NO loss accelerate the progression of diabetic and non-diabetic CKD, soluble guanylate cyclase (sGC) activators represent potential novel therapeutic interventions in CKD.

Methods

Two wks after 3/4 nephrectomy, male rats were instrumented for chronic BP radiotelemetry and RBF recordings and started on a 4% NaCl diet. Conscious BP and RBF recordings (1-2 hr; 2-4/wk) were initiated 1 wk later and continued over 3 wks while they were sequentially receiving: vehicle only by gavage (5 ml/kg), a low and a high dose of either the sGC activator (BR-11257) (3,10 mg/kg), enalapril (20,50 mg/kg) or the combination (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 developed in our lab.

Results

Table (mean ± SEM)
In this CKD model with volume (salt) dependent hypertension (HTN), BR-11257 but not enalapril significantly reduced BP and RVR (high dose), but in combination the two were synergistic. Effects on RBF were more variable. No adverse effect on AR ability to buffer spontaneous BP fluctuations was observed with any of the regimens.

Conclusion

These data suggest that sGC activators may have significant therapeutic potential in CKD states with volume dependent and/or RAS blockade resistant HTN that merit further investigation.

ParameterVehicle
(n=10)
BR-11257
(n-10)
Enalapril
(n=10)
BR-11257 + Enalapril
(n=9)
Baseline MAP
(mmHg)
140 ± 4.7131 ± 4.9136 ± 3.9127 ± 3.5
Low dose
(Δ %)
↑ 9 ± 2.2↓ 2 ± 3.1 δ↑ 7 ± 3.5↓ 15 ± 2.8 †
High dose
(Δ %)
↑ 13 ± 3.1↓ 9 ± 4.5 *↑ 9 ± 3.9↓ 20 ± 3.0 δ
Baseline RBF
(ml/min)
16 ± 2.817 ± 2.516 ± 2.519 ± 3.8
Low dose
(Δ %)
0 ± 7.1↑ 11 ± 6.7↑ 17 ± 8.2↑ 13 ± 6.0
High dose
(Δ %)
↑ 4 ± 6.5↑ 11 ± 8.7↑ 17 ± 5.0↑ 21 ± 8.1
Baseline RVR
(mmHg/ml/min)
11 ± 1.69 ± 1.211 ± 1.79 ± 1.3
Low dose
(Δ %)
↑ 15 ± 10.4↓ 7 ± 7.3↓ 4 ± 7.9↓ 23 ± 4.3 *
High dose
(Δ %)
↑ 14 ± 8.1↓ 12 ± 8.8 *↓ 8 ± 5.7↓ 30 ± 6.9 *

p < 0.05 maximum * vs vehicle; δ vs vehicle and enalapril; † vs. all other groups

Funding

  • Commercial Support