title: Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia.
abstract: The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3'5'-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3'5'-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves. Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted. Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall. Preemption of oxidative stress initiated by "consumptive" oxidation of nitric oxide stabilizes the vascular endothelium and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 3'5'-cyclic monphosphate offsets the extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented. One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician of impending fetal compromise. Fetal growth and vital organ maturation can continue. As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed. The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will help restore them fiscally.
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, 1313 21st Ave. So. 504 Oxford House, Nashville, Tennessee, USA. john.downing@vanderbilt.edu
authors.forename: J W
authors.initials: JW
authors.lastname: Downing
authors.forename: R
authors.initials: R
authors.lastname: Ramasubramanian
authors.forename: R F
authors.initials: RF
authors.lastname: Johnson
authors.forename: B H
authors.initials: BH
authors.lastname: Minzter
authors.forename: R L
authors.initials: RL
authors.lastname: Paschall
authors.forename: H W
authors.initials: HW
authors.lastname: Sundell
authors.forename: B
authors.initials: B
authors.lastname: Engelhardt
authors.forename: R
authors.initials: R
authors.lastname: Lewis
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008954:Models, Biological; D009102:Multiple Organ Failure / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011225:Pre-Eclampsia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D011247:Pregnancy; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human