Phosphodiesterase‐5 Inhibitors in Pulmonary Arterial Hypertension

Ghofrani, Hossein Ardeschir; Seeger, Werner; Grimminger, Friedrich

doi:10.1002/9780470997390.ch6

Cited by 3 publications

(2 citation statements)

References 132 publications

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“…Recently, imatinib, an effective agent in chronic myelogenous leukemia with PDGFR and c-Kit inhibitory activity, showed a significant survival effect in a conventional monocrotaline-induced rodent model of PH (48) and objective evidence of clinical improvement in two advanced PH patients (15,41). These findings and now the results of this study justify further development of antineoplastic kinase inhibitors of vascular cell proliferation and angiogenesis as future PH therapies (12)(13)(14)16). …”

Section: Discussionmentioning

confidence: 56%

Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Moreno‐Vinasco

Gomberg‐Maitland

Maitland

et al. 2008

Physiological Genomics

100

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Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics 33: 278 -291, 2008. First published February 26, 2008 doi:10.1152/physiolgenomics.00169.2007.-Pulmonary hypertension (PH) and cancer pathology share growth factor-and MAPK stressmediated signaling pathways resulting in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. In this study, we assessed sorafenib, an antineoplastic agent and inhibitor of multiple kinases important in angiogenesis [VEGF receptor (VEGFR)-1-3, PDGF receptor (PDGFR)-␤, Raf-1 kinase] as a potential PH therapy. Two PH rat models were used: a conventional hypoxia-induced PH model and an augmented PH model combining dual VEGFR-1 and -2 inhibition (SU-5416, single 20 mg/kg injection) with hypoxia. In addition to normoxiaexposed control animals, four groups were maintained at 10% inspired O 2 fraction for 3.5 wk (hypoxia/vehicle, hypoxia/SU-5416, hypoxia/ sorafenib, and hypoxia/SU-5416/sorafenib). Compared with normoxic control animals, rats exposed to hypoxia/SU-5416 developed hemodynamic and histological evidence of severe PH while rats exposed to hypoxia alone displayed only mild elevations in hemodynamic values (pulmonary vascular and right ventricular pressures). Sorafenib treatment (daily gavage, 2.5 mg/kg) prevented hemodynamic changes and demonstrated dramatic attenuation of PH-associated vascular remodeling. Compared with normoxic control rats, expression profiling (Affymetrix platform) of lung RNA obtained from hypoxia [false discovery rate (FDR) 6.5%]-and hypoxia/SU-5416 (FDR 1.6%)-challenged rats yielded 1,019 and 465 differentially regulated genes (fold change Ͼ1.4), respectively. A novel molecular signature consisting of 38 differentially expressed genes between hypoxia/SU-5416 and hypoxia/SU-5416/sorafenib (FDR 6.7%) was validated by either real-time RT-PCR or immunoblotting. Finally, immunoblotting studies confirmed the upregulation of the MAPK cascade in both PH models, which was abolished by sorafenib. In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target. microarrays; SU-5416; bioinformatics PULMONARY ARTERIAL HYPERTENSION (PH) is characterized by a progressive increase in pulmonary arterial pressure (PAP) with a mean pressure of Ͼ25 mmHg at rest or 30 mmHg during exercise (43), with severe PH exhibiting PAP values Ͼ50 mmHg (2, 59). Severe PH manifests as both an acute and a chronic presentation, with chronic PH leading to progressive right ventricular (RV) systolic pressure overload and ventricular dilatation, resulting in gradual RV dysfunction, heart failure, and death (21). Idiopathic PH has an estimated annual incidence of 1-2 per million (1) with mutations of the bone morphogenetic protein receptor type 2 gene (BMPR2) identified in ϳ50% of cases of familial PH (7). However, because only 20% of persons with a BMPR2 mutation develop PH (32), external stimuli, coupled with a susceptible genetic profile,...

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Section: Discussionmentioning

confidence: 56%

Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Moreno‐Vinasco

Gomberg‐Maitland

Maitland

et al. 2008

Physiological Genomics

100

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“…NO is generated by nitric oxide synthases (NOS) 67 . Three known isoforms of NOS are neuronal, inducible (iNOS), endothelial (eNOS) nitric oxide synthase 88 . Studies have demonstrated that NO that is produced by eNOS is the primary cause of pulmonary vasodilation.…”

Section: Resultsmentioning

confidence: 99%

Pulmonary hypertension associated with cardiopulmonary bypass and cardiac surgery

Fayad

Sellke

Feng

2022

Journal of Cardiac Surgery

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Background and Aim Pulmonary hypertension (PH) is frequently associated with cardiovascular surgery and is a common complication that has been observed after surgery utilizing cardiopulmonary bypass (CPB). The purpose of this review is to explain the characteristics of PH, the mechanisms of PH induced by cardiac surgery and CPB, treatments for postoperative PH, and future directions in treating PH induced by cardiac surgery and CPB using up‐to‐date findings. Methods The PubMed database was utilized to find published articles. Results There are many mechanisms that contribute to PH after cardiac surgery and CPB which involve pulmonary vasomotor dysfunction, cyclooxygenase, the thromboxane A2 and prostacyclin pathway, the nitric oxide pathway, inflammation, and oxidative stress. Furthermore, there are several effective treatments for postoperative PH within different types of cardiac surgery. Conclusions By possessing a deep understanding of the mechanisms that contribute to PH after cardiac surgery and CPB, researchers can develop treatments for clinicians to use which target the mechanisms of PH and ultimately reduce and/or eliminate postoperative PH. Additionally, learning about the most up‐to‐date studies regarding treatments can allow clinicians to choose the best treatments for patients who are undergoing cardiac surgery and CPB.

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Dietary arginine: metabolic, environmental, immunological and physiological interrelationships

Khajali

Wideman

2010

World's Poultry Science Journal

126

117

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Phosphodiesterase‐5 Inhibitors in Pulmonary Arterial Hypertension

Cited by 3 publications

References 132 publications

Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Pulmonary hypertension associated with cardiopulmonary bypass and cardiac surgery

Dietary arginine: metabolic, environmental, immunological and physiological interrelationships

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