Cardiology Research, Bayer HealthCare, Wuppertal, Germany.
PLoS One. 2011;6(7):e21853. doi: 10.1371/journal.pone.0021853. Epub 2011 Jul 18.
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.
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.
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.
直接刺激可溶性鸟苷酸环化酶（sGC）是治疗与内皮功能障碍相关的各种心血管疾病的一种新兴治疗方法。新型 sGC 刺激剂，包括 riociguat（BAY 63-2521），具有双重作用模式：它们使 sGC 对内源性产生的一氧化氮（NO）敏感，并且还可以独立于 NO 直接刺激 sGC。关于它们在实验性恶性高血压中对组织重塑和变性以及存活的影响知之甚少。
在高盐饮食的 Dahl 盐敏感大鼠中评估死亡率、血液动力学以及组织重塑和变性的生物标志物，并用 riociguat（3 或 10 mg/kg/d）治疗 14 周。Riociguat 显著减轻了全身性高血压，改善了收缩期心脏功能，并将存活率从 33%提高到 85%。心脏和肾脏的组织学检查表明，riociguat 显著改善了纤维化的组织重塑和变性。相应地，心肌和肾皮质中促纤维化生物标志物骨桥蛋白（OPN）、基质金属蛋白酶抑制剂-1（TIMP-1）和纤溶酶原激活物抑制剂-1（PAI-1）的 mRNA 表达被 riociguat 减弱。此外，riociguat 降低了 OPN、TIMP-1 和 PAI-1 的血浆和尿液水平。
riociguat 刺激 sGC 可显著改善存活率，并减轻全身性高血压和收缩功能障碍，以及在压力和容量超负荷的啮齿动物模型中改善心肌和肾皮质的纤维化组织重塑。这些发现表明 sGC 刺激剂在与心血管和肾功能受损相关的疾病中有治疗潜力。
