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e despite continued exposure to the vasodilating stimulus [14, 26, 32]. Teleologically, this active opposition to prolonged pulmonary vasodilation in the fetal lung prevents a steal of blood flow from the placenta, the fetal organ of gas exchange. However, endothelium-independent agents that directly increase smooth muscle cell cGMP levels were found to cause sustained pulmonary vasodilation during prolonged infusions [33, 34]. Mechanisms contributing to this time-dependent autoregulatory response are unknown, but may include decreased production of endogenous nitric oxide by the endothelial and smooth muscle cells, down-regulation of guanylate cyclase, or increased release of vasoconstricting mediators such as endothelin-1.Conclusion and PerspectivesIn conclusion, we found that sildenafil induces a potent but transient pulmonary vasodilation in the fetus. Although the effects of sildenafil on the basal pulmonary vascular tone are transient, sildenafil causes prolonged changes in pulmonary vasoreactivity. Especially, sildenafil increases the pulmonary hemodynamic responses to increased fetal PaO2 and to acute DA compression. These results support the hypothesis that PDE5 is involved in the control of the basal pulmonary vascular tone and in the regulation of the pulmonary vascular reactivity to birth-related events during the perinatal life.Pulmonary hypertension is associated with elevated pulmonary vascular tone and abnormal pulmonary vasoreactivity. Especially, the pulmonary vascular response to increased O2 tension and to change in hemodynamic forces are markedly impaired in persistent pulmonary hypertension of the newborn [7, 9]. Chronic pulmonary hypertension impairs flow-induced vasodilation and augments a myogenic response, causing a paradoxical vasoconstriction to increase in pulmonary pressure [9]. As sildenafil increases the pulmonary vascular response to birth-related stimuli, we speculate that PDE5 inhibitor treatment may have a therapeutic impact on perinatal pulmonary hypertension.Back to Article OutlineThis work was supported by Grants from Dlgation la Recherche du CHRU de Lille, Facult de Mdecine de Lille, Universit de Lille II, Fondation de France, Fondation de lAvenir, and by Journes Francophones de Recherche en Nonatologie.Back to Article OutlineReferences
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Handb Exp Pharmacol. 2009;(191):277-308. doi: 10.1007/978-3-540-68964-5_13.NO-independent, haem-dependent soluble guanylate cyclase stimulators.Stasch JP, Hobbs AJ.SourceBayer Schering Pharma AG, Cardiology Research, Pharma Research Center, Wuppertal, 42096, Germany. [email protected] nitric oxide (NO) signalling pathway is altered in cardiovascular diseases, including systemic and pulmonary hypertension, stroke, and atherosclerosis. The vasodilatory properties of NO have been exploited for over a century in cardiovascular disease, but NO donor drugs and inhaled NO are associated with significant shortcomings, including resistance to NO in some disease states, the development of tolerance during long-term treatment, and non-specific effects such as post-translational modification of proteins. The development of pharmacological agents capable of directly stimulating the NO receptor, soluble guanylate cyclase (sGC), is therefore highly desirable. The benzylindazole compound YC-1 was the first sGC stimulator to be identified; this compound formed a lead structure for the development of optimized sGC stimulators with improved potency and specificity for sGC, including CFM-1571, BAY 41-2272, BAY 41-8543, and BAY 63-2521. In contrast to the NO- and haem-independent sGC activators such as BAY 58-2667, these compounds stimulate sGC activity independent of NO and also act in synergy with NO to produce anti-aggregatory, anti-proliferative, and vasodilatory effects. Recently, aryl-acrylamide compounds were identified independent of YC-1 as sGC stimulators; although structurally dissimilar to YC-1, they have a similar mode of action and promote smooth muscle relaxation. Pharmacological stimulators of sGC may be beneficial in the treatment of a range of diseases, including systemic and pulmonary hypertension, heart failure, atherosclerosis, erectile dysfunction, and renal fibrosis. An sGC stimulator, BAY 63-2521, is currently in clinical development as an oral therapy for patients with pulmonary hypertension. It has demonstrated efficacy in a proof-of-concept study, reducing pulmonary vascular resistance and increasing cardiac output from baseline. A full, phase 2 trial of BAY 63-2521 in pulmonary hypertension is underway.PMID: 19089334 [PubMed - indexed for MEDLINE] Publication Types, MeSH Terms, SubstancesPublication Types
- Review
MeSH Terms
- Acrylamides/pharmacology
- Animals
- Cardiovascular Diseases/drug therapy
- Cardiovascular Diseases/physiopathology
- Clinical Trials as Topic
- Enzyme Activators/pharmacology*
- Guanylate Cyclase/drug effects*
- Guanylate Cyclase/metabolism
- Heme/metabolism*
- Humans
- Indazoles/pharmacology
- Nitric Oxide/metabolism
- Pyrimidines/pharmacology
- Receptors, Cytoplasmic and Nuclear/drug effects*
- Receptors, Cytoplasmic and Nuclear/metabolism
- Signal Transduction
Substances
- Acrylamides
- Enzyme Activators
- Indazoles
- Pyrimidines
- Receptors, Cytoplasmic and Nuclear
- Nitric Oxide
- Heme
- Guanylate Cyclase
- soluble guanylyl cyclase
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- Review NO- and haem-independent soluble guanylate cyclase
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Schmidt HH, Schmidt PM, Stasch JP. Handb Exp Pharmacol. 2009; (191):309-39.
- Review Nitric oxide-independent stimulation of soluble guanylate cyclase with BAY 41-2272 in cardiovascular disease.[Cardiovasc Drug Rev. 2007]Review Nitric oxide-independent stimulation of soluble guanylate cyclase with BAY 41-2272 in cardiovascular disease.Boerrigter G, Burnett JC Jr. Cardiovasc Drug Rev. 2007 Spring; 25(1):30-45.
- Review Exploring the potential of NO-independent stimulators and activators of soluble guanylate cyclase for the medical treatment of erectile dysfunction.[Curr Pharm Des. 2010]Review Exploring the potential of NO-independent stimulators and activators of soluble guanylate cyclase for the medical treatment of erectile dysfunction.Gur S, Kadowitz PJ, Hellstrom WJ. Curr Pharm Des. 2010 May; 16(14):1619-33.
- Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension.[ChemMedChem. 2009]Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension.Mittendorf J, Weigand S, Alonso-Alija C, Bischoff E, Feurer A, Gerisch M, Kern A, Knorr A, Lang D, Muenter K, et al. ChemMedChem. 2009 May; 4(5):853-65.
- Soluble guanylate cyclase stimulators in pulmonary hypertension.[Handb Exp Pharmacol. 2013]Soluble guanylate cyclase stimulators in pulmonary hypertension.Stasch JP, Evgenov OV. Handb Exp Pharmacol. 2013; 218:279-313.
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- Thrombin has biphasic effects on the nitric oxide-cGMP pathway in endothelial cells and contributes to experimental pulmonary hypertension.[PLoS One. 2013]Thrombin has biphasic effects on the nitric oxide-cGMP pathway in endothelial cells and contributes to experimental pulmonary hypertension.Nickel KF, Laux V, Heumann R, von Degenfeld G. PLoS One. 2013; 8(6):e63504. Epub 2013 Jun 13.
- Stimulators of soluble guanylyl cyclase: future clinical indications.[Ochsner J. 2013]Stimulators of soluble guanylyl cyclase: future clinical indications.Nossaman BD, Kadowitz PJ. Ochsner J. 2013 Spring; 13(1):147-56.
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- NO-independent, haem-dependent soluble guanylate cyclase stimulators.NO-independent, haem-dependent soluble guanylate cyclase stimulators.Handb Exp Pharmacol. 2009 ;(191):277-308. doi: 10.1007/978-3-540-68964-5_13.
PubMedEffects of phosphodiesterase 5 inhibitor on pulmonary vascular reactivity in the...Effects of phosphodiesterase 5 inhibitor on pulmonary vascular reactivity in the fetal lamb.Ann Thorac Surg. 2006 Mar ;81(3):935-42.PubMed16488698[uid] (1)PubMed
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