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.
Kalk
Philipp
P
Department of Pharmacology and Toxicology, Center for Cardiovascular Research, Charité, Campus Mitte, Hessische Str. 3-4, Berlin D-10115, Germany.
Godes
Michael
M
Relle
Katharina
K
Rothkegel
Christiane
C
Hucke
Andreas
A
Stasch
Johannes-Peter
JP
Hocher
Berthold
B
D000419:Albuminuria / Q000188:drug therapy; D000818:Animals; D001565:Benzoates / Q000097:blood / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000378:metabolism; D018450:Disease Progression; D006162:Guanylate Cyclase / Q000502:physiology*; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000097:blood; D009392:Nephrectomy; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D001565:Benzoates; D020097:Natriuretic Peptide, Brain; D009569:Nitric Oxide; C480588:BAY 58-2667; D003404:Creatinine; D006162:Guanylate Cyclase