Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Persistent pulmonary hypertension secondary to meconium aspiration syndrome is an important cause of morbidity and mortality in the neonatal population. We investigated the use of the phosphodiesterase-5 inhibitor sildenafil, in its intravenous form, as a pulmonary vasodilator in a model of meconium aspiration syndrome. Pulmonary hypertension was induced in 18 piglets, by endotracheal instillation of human meconium, 6 piglets subsequently received an infusion of intravenous sildenafil for 2 hours, 6 received inhaled nitric oxide for 2 hours, and 6 control animals received no additional intervention. Meconium aspiration increased pulmonary vascular resistance by 70%, and increased oxygenation index by over 100%. Pulmonary vascular resistance remained elevated for the remainder of the study period in control animals. Inhaled nitric oxide reduced the pulmonary vascular resistance by 40% after 2 hours of treatment; intravenous sildenafil completely reversed the increase in pulmonary vascular resistance within 1 hour of commencing the infusion. Neither agent had an effect on systemic hemodynamics. Sildenafil also increased cardiac output by 30%, but while doing so did not adversely influence oxygenation. Intravenous sildenafil is a selective and highly effective pulmonary vasodilator, which is at least as effective as inhaled nitric oxide, in this model of neonatal persistent pulmonary hypertension.
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PMID:Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. 1195 51

Nitric oxide (NO), an important endogenous signalling molecule released from vascular endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in smooth muscle cells that reduce intracellular Ca2+ levels to inhibit both contractility and proliferation. The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing it into inactive 5'-GMP. Small molecule PDE5 inhibitors (PDE5is) such as sildenafil prolong the availability of cGMP and so enhance NO-mediated signalling. PDE5is are the first line treatment for erectile dysfunction but are also now approved for treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension in neonates (PPHN) is currently treated with inhaled NO but this is an expensive option and around 1/3 of newborns are unresponsive resulting in the need for alternative approaches. Here we summarize the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile dysfunction and PAH, and then critically review current evidence for the utility of further repurposing of sildenafil as a treatment for PPHN.
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PMID:Repurposing of the PDE5 inhibitor sildenafil for treatment of persistent pulmonary hypertension in neonates. 3296 19