Abstract: FR-PO190

Renal Hemodynamic Effects of Sgc Activation Versus ACE Inhibition in Conscious Obese Diabetic ZSF1 Rats

Session Information

Category: Hypertension

  • 1103 Vascular Biology and Dysfunction

Authors

  • Bidani, Anil K., Loyola University Med Ctr and Hines VA Hospital, Maywood, Illinois, United States
  • Williamson, Geoffrey A., Illinois Institute of Technology, Chicago, Alabama, United States
  • Polichnowski, Aaron J., East Tennessee State University, Johnson City, Tennessee, United States
  • Sethupathi, Perriannan, Loyola University Medical Center, Maywood, Illinois, United States
  • Benardeau, Agnes M, Bayer AG, Wuppertal, Germany
  • Eitner, Frank, Bayer AG, Wuppertal, Germany
  • Griffin, Karen A., Loyola University Med Ctr and Hines VA Hospital, Maywood, Illinois, United States
Background

Substantial evidence indicates that endothelial dysfunction and/or NO loss accelerates the progression of diabetic and non-diabetic chronic kidney disease (CKD). Therefore, soluble guanylate cyclase (sGC) modulators are being developed as potential novel therapeutic interventions in CKD, but only limited data are available as to their renal hemodynamic effects and none in the unanesthetized rodent disease models.

Methods

Conscious chronically instrumented 12-14 wk old 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 enalapril (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 (AR indices [fractional change in RBF / fractional change in MAP] are calculated for ~500 adjacent pairs of short segments of 2.5 sec length/rat, which exhibit a difference in MAP of at least 5mmHg, SSARI).

Results

Table (mean + SEM)

Similar to what we have observed in normal rats, at the dosages used, both agents reduced BP comparably. However, significantly greater dose-dependent renal vasodilation was observed with the sGC activator, but not enalapril. Although enalapril did reduce RVR at the higher dose, the increase in RBF did not reach statistical significance. AR buffering of spontaneous BP fluctuations was well preserved and not altered by either agent.

Conclusion

Collectively, the BP and renal hemodynamic effects of sGC activation in the conscious ZSF1 rat suggest that sGC modulators may have significant therapeutic utility in CKD states meriting additional investigations directly addressing CKD progression.

 sGC Activator, BAY-543 (n=9) Enalapril (n=9)
 Vehicle3 mg/kg10 mg/kg Vehicle20 mg/kg50 mg/kg
MAP (mmHg)130.8±2.2123.3±3.0*114.3±1.6*# 135.1±2.4127.7±2.9*118.8±3.3*#
RBF (ml/min)9.3±0.911.1±0.9*13.3±1.1*# 8.6±0.98.9±0.89.7±1.0
RVR (mmHg/ml.min)15.5±1.612.0±1.2*9.3±1.0*# 17.0±1.715.2±1.113.4±1.3*
SSARI0.20±0.060.21±0.070.19±0.08 0.19±0.070.25±0.080.32±0.06

*p<0.05 minimum vs. vehicle; # p<0.05 minimum vs lower dose (repeated measures ANOVA)

Funding

  • Commercial Support