Key result
sGC agonists increase GFR when MAP drops <10% but decrease GFR during larger reductions.
Why the study?
Most effects of nitric oxide on glomerular and tubular function are mediated through sGC, but whether sGC agonists mimic these effects is unknown.
Do sGC agonists (BAY 41-2272 and runcaciguat) affect blood pressure and kidney function in normal and diabetic rats?
Do sGC agonists (BAY 41-2272 and runcaciguat) affect blood pressure and kidney function in normal and diabetic rats?
sGC agonists acutely reduce blood pressure and have a direct tendency to increase GFR when MAP reductions are <10%, but larger MAP declines override this effect.
sGC agonists may preserve GFR at modest MAP reductions in diabetic rats; leaves open translation to human CKD.
INTRODUCTION: Agonists of soluble guanylate cyclase (sGC) are being developed as treatment for cardiovascular disease. Most effects of nitric oxide (NO) on glomerular and tubular function are mediated through sGC but whether sGC agonists mimic these effects is unknown. METHODS: Renal clearance and micropuncture studies were performed in Wistar-Froemter rats (WF), with or without streptozotocin diabetes (STZ-WF), and in Goto-Kakizaki rats (GK) with mild type-2 diabetes to test for acute effects of the sGC “stimulator” BAY 41-2272, which synergizes with endogenous NO, and the “activator” runcaciguat, which generates cGMP independent of NO. RESULTS: Both sGC agonists reduced arterial blood pressure (MAP). For MAP reductions <10% the drugs increased GFR in WF and STZ-WF but not in GK. Larger MAP reductions outweighed this effect and GFR declined, with better preserved GFR in STZ-WF. Changes in GFR could not be accounted for by changes in RBF, suggesting parallel changes in ultrafiltration pressure and/or ultrafiltration coefficient. The doses chosen for micropuncture in WF and GK reduced MAP by 2–10% and the net effect on single nephron GFR and ultrafiltration pressure was neutral. Effects of the drugs on tubular reabsorption were dominated by declining MAP and no natriuretic effect observed at any dose. DISCUSSION/CONCLUSION: sGC agonists impact kidney function directly and because they reduce MAP. The direct tendency to increase GFR is most apparent for MAP reductions <10%. The direct effect is otherwise subtle and overridden when MAP declines more. Effects of sGC agonists on tubular reabsorption are dominated by effects on MAP.
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Patel et al. (2022) studied Normal and diabetic rats. sGC stimulator BAY 41-2272 and sGC activator runcaciguat was evaluated on Arterial blood pressure (MAP) and glomerular filtration rate (GFR). Soluble guanylate cyclase agonists reduced arterial blood pressure and increased GFR for MAP reductions <10%, but larger MAP reductions overrode this direct effect and caused GFR to decline.
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