Riociguat prevents fibrotic tissue remodelling and improves survival in salt-sensitive Dahl rats
BMC Pharmacology(2011)
Abstract
Direct stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of cardiopulmonary disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat, 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. 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. 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. 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 providing organ protection in diseases associated with impaired cardio-renal functions.
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Key words
Nitric Oxide,Tissue Remodelling,Renal Cortex,Guanylate Cyclase,Systemic Hypertension
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