Dataset Information

Treatment Selection in Pulmonary Arterial Hypertension: Phosphodiesterase Type 5 Inhibitors versus Soluble Guanylate Cyclase Stimulator.

ABSTRACT: Pulmonary arterial hypertension is a chronic and life-threatening disease that if left untreated is fatal. Current therapies include stimulating the nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate axis, improving the prostacyclin pathway and inhibiting the endothelin pathway. Phosphodiesterase type 5 inhibitors, such as sildenafil, and the sGC stimulator riociguat are currently used in the treatment of pulmonary arterial hypertension. This article discusses the similarities and differences between phosphodiesterase type 5 inhibitors and sGC stimulator based on pharmacological action and clinical trials, and considers which is better for the treatment of pulmonary arterial hypertension.

SUBMITTER: Watanabe H

PROVIDER: S-EPMC6159440 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Treatment Selection in Pulmonary Arterial Hypertension: Phosphodiesterase Type 5 Inhibitors versus Soluble Guanylate Cyclase Stimulator.

Watanabe Hiroshi H

European cardiology 20180801 1

Pulmonary arterial hypertension is a chronic and life-threatening disease that if left untreated is fatal. Current therapies include stimulating the nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate axis, improving the prostacyclin pathway and inhibiting the endothelin pathway. Phosphodiesterase type 5 inhibitors, such as sildenafil, and the sGC stimulator riociguat are currently used in the treatment of pulmonary arterial hypertension. This article discusses the simila ...[more]

PMID: 30310468

Similar Datasets

Project description:BackgroundThe nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal-transduction pathway is impaired in many cardiovascular diseases, including pulmonary arterial hypertension (PAH). Riociguat (BAY 63-2521) is a stimulator of sGC that works both in synergy with and independently of NO to increase levels of cGMP. The aims of this study were to investigate the role of NO-sGC-cGMP signaling in a model of severe PAH and to evaluate the effects of sGC stimulation by riociguat and PDE5 inhibition by sildenafil on pulmonary hemodynamics and vascular remodeling in severe experimental PAH.Methods and resultsSevere angioproliferative PAH was induced in rats by combined exposure to the vascular endothelial growth factor receptor antagonist SU5416 and hypoxia (SUHx). Twenty-one days thereafter rats were randomized to receive either riociguat (10 mg/kg/day), sildenafil (50 mg/kg/day) or vehicle by oral gavage, for 14 days until the day of the terminal hemodynamic measurements. Administration of riociguat or sildenafil significantly decreased right ventricular systolic pressure (RVSP). Riociguat significantly decreased RV hypertrophy (RVH) (0.55 ± 0.02, p<0.05), increased cardiac output (60.8 ± .8 mL/minute, p<0.05) and decreased total pulmonary resistance (4.03 ± 0.3 mmHg min(-1) ml(-1) 100 g BW, p<0.05), compared with sildenafil and vehicle. Both compounds significantly decreased the RV collagen content and improved RV function, but the effects of riociguat on tricuspid annular plane systolic excursion and RV myocardial performance were significantly better than those of sildenafil (p<0.05). The proportion of occluded arteries was significantly lower in animals receiving riociguat than in those receiving vehicle (p<0.05); furthermore, the neointima/media ratio was significantly lower in those receiving riociguat than in those receiving sildenafil or vehicle (p<0.05).ConclusionRiociguat and sildenafil significantly reduced RVSP and RVH, and improved RV function compared with vehicle. Riociguat had a greater effect on hemodynamics and RVH than sildenafil.

Project description:Background: Lower-limb peripheral artery disease (PAD) is one of the major complications of diabetes mellitus. PAD is associated with poor limb and cardiovascular prognoses, along with a dramatic decrease in life expectancy. Despite major medical advances in the treatment of diabetes, a substantial therapeutic gap remains in the PAD population. Praliciguat is an orally available soluble guanylate cyclase (sGC) stimulator that has been reported both pre-clinically and in early-stage clinical trials to have favorable effects in metabolic and hemodynamic outcomes, suggesting that it may have a potential beneficial effect in PAD. Objective: We evaluated the effect of praliciguat on hind limb ischemia (HLI) recovery in a mouse model of type 2 diabetes. Methods: HLI was induced in leptin receptor-deficient (Leprdb/db) mice by ligation and excision of the left femoral artery. Praliciguat (10 mg/kg/day) was administered in the diet starting 3 days before surgery. Results: 28 days after surgery, ischemic foot perfusion and function parameters were better in praliciguat-treated mice than in vehicle controls. Improved ischemic foot perfusion was not associated with either improved traditional cardiovascular risk factors (i.e., weight, glycemia) or increased angiogenesis. However, treatment with praliciguat significantly increased arteriole diameter, decreased intercellular adhesion molecule 1 (ICAM1) expression, and prevented the accumulation of oxidative pro-angiogenic and pro-inflammatory muscle fibers. While investigating the mechanism underlying the beneficial effects of praliciguat therapy, we found that praliciguat significantly downregulated Myh2 and Cxcl12 mRNA expression in cultured myoblasts and that conditioned medium form praliciguat-treated myoblast decreased ICAM-1 mRNA expression in endothelial cells. These results suggest that praliciguat therapy may decrease ICAM-1 expression in endothelial cells by downregulating Cxcl12 in myocytes. Conclusion: Our results demonstrated that praliciguat promotes blood flow recovery in the ischemic muscle of mice with type 2 diabetes, at least in part by increasing arteriole diameter and by downregulating ICAM-1 expression.

Dataset Information

Treatment Selection in Pulmonary Arterial Hypertension: Phosphodiesterase Type 5 Inhibitors versus Soluble Guanylate Cyclase Stimulator.

Publications

Treatment Selection in Pulmonary Arterial Hypertension: Phosphodiesterase Type 5 Inhibitors versus Soluble Guanylate Cyclase Stimulator.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets