Limits...
Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats.

Geschka S, Kretschmer A, Sharkovska Y, Evgenov OV, Lawrenz B, Hucke A, Hocher B, Stasch JP - PLoS ONE (2011)

Bottom Line: In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1.Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload.These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.

View Article: PubMed Central - PubMed

Affiliation: Cardiology Research, Bayer HealthCare, Wuppertal, Germany.

ABSTRACT

Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension.

Methods and results: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1.

Conclusions: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.

Show MeSH

Related in: MedlinePlus

Effects of riociguat on mRNA expression of osteopontin (OPN), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in the left ventricle and the renal cortex in the vehicle (n = 7) - and riociguat-treated (3 or 10 mg/kg/d, n = 11 per group) Dahl/ss rats maintained on a high-salt diet.Healthy, age-matched animals were used as controls (n = 10). Data are mean±SEM; *p<0.05 vs. the vehicle-treated animals; #p<0.05 vs. healthy controls.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3138745&req=5

pone-0021853-g002: Effects of riociguat on mRNA expression of osteopontin (OPN), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in the left ventricle and the renal cortex in the vehicle (n = 7) - and riociguat-treated (3 or 10 mg/kg/d, n = 11 per group) Dahl/ss rats maintained on a high-salt diet.Healthy, age-matched animals were used as controls (n = 10). Data are mean±SEM; *p<0.05 vs. the vehicle-treated animals; #p<0.05 vs. healthy controls.

Mentions: The gene expression of the pro-fibrotic biomarkers OPN, TIMP-1 and PAI-1 were determined in the hearts and kidneys of the pressure- and volume-overloaded Dahl/ss rats (Figure 2). Compared to healthy control animals, the relative increase in mRNA expression of the pro-fibrotic biomarkers was detected in all tissue samples in the vehicle group. In particular, mRNA expression of PAI-1 and TIMP-1 was significantly increased in the renal cortex (p<0.05). Treatment with riociguat prevented the mRNA up-regulation of OPN, TIMP-1, and PAI-1 in the renal cortex (p<0.05). Riociguat also attenuated mRNA expression of OPN, TIMP-1, and PAI-1 in the left ventricle.


Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats.

Geschka S, Kretschmer A, Sharkovska Y, Evgenov OV, Lawrenz B, Hucke A, Hocher B, Stasch JP - PLoS ONE (2011)

Effects of riociguat on mRNA expression of osteopontin (OPN), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in the left ventricle and the renal cortex in the vehicle (n = 7) - and riociguat-treated (3 or 10 mg/kg/d, n = 11 per group) Dahl/ss rats maintained on a high-salt diet.Healthy, age-matched animals were used as controls (n = 10). Data are mean±SEM; *p<0.05 vs. the vehicle-treated animals; #p<0.05 vs. healthy controls.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3138745&req=5

pone-0021853-g002: Effects of riociguat on mRNA expression of osteopontin (OPN), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in the left ventricle and the renal cortex in the vehicle (n = 7) - and riociguat-treated (3 or 10 mg/kg/d, n = 11 per group) Dahl/ss rats maintained on a high-salt diet.Healthy, age-matched animals were used as controls (n = 10). Data are mean±SEM; *p<0.05 vs. the vehicle-treated animals; #p<0.05 vs. healthy controls.
Mentions: The gene expression of the pro-fibrotic biomarkers OPN, TIMP-1 and PAI-1 were determined in the hearts and kidneys of the pressure- and volume-overloaded Dahl/ss rats (Figure 2). Compared to healthy control animals, the relative increase in mRNA expression of the pro-fibrotic biomarkers was detected in all tissue samples in the vehicle group. In particular, mRNA expression of PAI-1 and TIMP-1 was significantly increased in the renal cortex (p<0.05). Treatment with riociguat prevented the mRNA up-regulation of OPN, TIMP-1, and PAI-1 in the renal cortex (p<0.05). Riociguat also attenuated mRNA expression of OPN, TIMP-1, and PAI-1 in the left ventricle.

Bottom Line: In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1.Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload.These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.

View Article: PubMed Central - PubMed

Affiliation: Cardiology Research, Bayer HealthCare, Wuppertal, Germany.

ABSTRACT

Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension.

Methods and results: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1.

Conclusions: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.

Show MeSH
Related in: MedlinePlus