Effect of Sildenafil on Pulmonary Circulation and Cardiovascular Function in Near-Term Fetal Sheep During Hypoxemia.

Abstract

Sildenafil is a potential new treatment for placental insufficiency in human pregnancies as it reduces the breakdown of vasodilator nitric oxide. Pulmonary vasodilatation is observed in normoxemic fetuses following sildenafil administration. Placental insufficiency often leads to fetal hypoxemia that can cause pulmonary vasoconstriction and fetal cardiac dysfunction as evidenced by reduced isovolumic myocardial velocities. We tested the hypotheses that sildenafil, when given directly to the hypoxemic fetus, reverses reactive pulmonary vasoconstriction, increases left ventricular cardiac output by increasing pulmonary venous return, and ameliorates hypoxemic myocardial dysfunction. We used an instrumented sheep model. Fetuses were made hypoxemic over a mean (standard deviation) duration of 41.3 (9.5) minutes and then given intravenous sildenafil or saline infusion. Volume blood flow through ductus arteriosus was measured with an ultrasonic transit-time flow probe. Fetal left and right ventricular outputs and lung volume blood flow were calculated, and ventricular function was examined using echocardiography. Lung volume blood flow decreased and the ductus arteriosus volume blood flow increased with hypoxemia. There was a significant reduction in left ventricular and combined cardiac outputs during hypoxemia in both groups. Hypoxemia led to a reduction in myocardial isovolumic velocities, increased ductus venosus pulsatility, and reduced left ventricular myocardial deformation. Direct administration of sildenafil to hypoxemic fetus did not reverse the redistribution of cardiac output. Furthermore, fetal cardiac systolic and diastolic dysfunction was observed during hypoxemia, which was not improved by fetal sildenafil treatment. In conclusion, sildenafil did not improve pulmonary blood flow or cardiac function in hypoxemic sheep fetuses.

• Authors: Amarnath Bhide, Leena Alanne, Juha Rasanen, Heikki Huhta, Juulia Junno, Merja Kokki, Tiina Erkinaro, Pasi Ohtonen, Mervi Haapsamo, Ganesh Acharya
• Journal: Reproductive sciences (Thousand Oaks, Calif.) (Reprod Sci) Vol. 26 Issue 3 Pg. 337-347 (03 2019) ISSN: 1933-7205 [Electronic] United States
• PMID: 29716434 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Vasodilator Agents
• Sildenafil Citrate

Topics

• Animals
• Cardiac Output
• Disease Models, Animal
• Female
• Hemodynamics (drug effects)
• Hypoxia (drug therapy, physiopathology)
• Placental Insufficiency (drug therapy)
• Pregnancy
• Pulmonary Circulation (drug effects)
• Sheep
• Sildenafil Citrate (administration & dosage)
• Vasodilator Agents (administration & dosage)