Department of Medicine, University of California San Diego, La Jolla, California, USA.
VA San Diego Healthcare System, San Diego, California, USA.
Nephron. 2023;147(5):281-300. doi: 10.1159/000526934. Epub 2022 Oct 20.
: 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.
: 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.
: 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.
可溶性鸟苷酸环化酶（sGC）激动剂被开发用于治疗心血管疾病。一氧化氮（NO）对肾小球和肾小管功能的大多数影响都是通过 sGC 介导的，但 sGC 激动剂是否模拟这些作用尚不清楚。
在 Wistar-Froemter 大鼠（WF）中进行了肾清除率和微穿刺研究，这些大鼠有无链脲佐菌素糖尿病（STZ-WF），以及在轻度 2 型糖尿病的 Goto-Kakizaki 大鼠（GK）中进行了研究，以测试 sGC“刺激剂”BAY 41-2272 的急性作用，该刺激剂与内源性 NO 协同作用，以及“激活剂”runcaciguat，该激活剂独立于 NO 产生 cGMP。
两种 sGC 激动剂均降低了动脉血压（MAP）。对于 MAP 降低<10％的药物，在 WF 和 STZ-WF 中增加了 GFR，但在 GK 中则没有增加。更大的 MAP 降低超过了这种作用，GFR 下降，STZ-WF 中 GFR 的保存更好。GFR 的变化不能用 RBF 的变化来解释，这表明超滤压和/或超滤系数发生了平行变化。在 WF 和 GK 中选择用于微穿刺的剂量将 MAP 降低了 2-10％，对单个肾小球 GFR 和超滤压的净影响为中性。药物对肾小管重吸收的影响主要受 MAP 下降的影响，在任何剂量下均未观察到利尿作用。
讨论/结论：sGC 激动剂直接影响肾脏功能，因为它们降低了 MAP。当 MAP 降低<10％时，直接增加 GFR 的趋势最为明显。否则，当 MAP 下降更多时，直接作用就很微妙，会被掩盖。sGC 激动剂对肾小管重吸收的影响主要受 MAP 影响。
