Riociguat treatment increased survival from 33% to 85% and attenuated systemic hypertension, systolic dysfunction, and fibrotic tissue remodeling in salt-sensitive Dahl rats.
Does riociguat improve survival and attenuate fibrotic tissue remodeling in Dahl salt-sensitive rats on a high salt diet?
In a rodent model of malignant hypertension, sGC stimulation with riociguat significantly improved survival and reduced cardiac and renal fibrotic remodeling.
Absolute Event Rate: 85% vs 33%
p-value: p=<0.05
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.
Geschka et al. (Mon,) conducted a other in Salt-sensitive hypertension and cardiac/renal end-organ damage (n=57). Riociguat vs. Vehicle was evaluated on Survival (p=<0.05). Riociguat treatment increased survival from 33% to 85% and attenuated systemic hypertension, systolic dysfunction, and fibrotic tissue remodeling in salt-sensitive Dahl rats.