NO‐independent activation of soluble guanylate cyclase prevents disease progression in rats with 5/6 nephrectomy

1 Chronic renal disease is associated with oxidative stress, reduced nitric oxide (NO) availability and soluble guanylate cyclase (sGC) dysfunction. Recently, we discovered BAY 58‐2667, a compound activating heme‐deficient or oxidized sGC in a NO‐independent manner. 2 We assessed potential of BAY 58‐2667 in preventing cardiac and renal target organ damage in rats with 5/6 nephrectomy. 3 Male Wistar rats were allocated to three groups: 5/6 nephrectomy, 5/6 nephrectomy treated with BAY 58‐2667 and sham operation. Study period was 18 weeks: blood pressure and creatinine clearance were assessed repeatedly. At study end blood samples were taken and hearts and kidneys harvested for histological studies. 4 BAY 58‐2667 markedly lowered blood pressure in animals with 5/6 nephrectomy (untreated versus treated animals: 189±14 versus 146±11 mmHg, P <0.001). Left ventricular weight, cardiac myocyte diameter as well as cardiac arterial wall thickness significantly decreased in comparison to untreated animals with 5/6 nephrectomy. Natriuretic peptide plasma levels were also improved by BAY 58‐2667. Kidney function and morphology as assessed by creatinine clearance, glomerulosclerosis, interstitial and perivascular fibrosis of intrarenal arteries were likewise significantly improved by BAY 58‐2667. 5 This is the first study showing that BAY 58‐2667 effectively lowers blood pressure, reduces left ventricular hypertrophy and slows renal disease progression in rats with 5/6 nephrectomy by targeting mainly oxidized sGC. Therefore, BAY 58‐2667 represents a novel pharmacological principle with potential clinical value in treatment of chronic renal disease.British Journal of Pharmacology (2006) 148 , 853–859. doi: 10.1038/sj.bjp.0706792