Pulmonary vascular effects of nitric oxide-cGMP augmentation in a model of chronic pulmonary hypertension in fetal and neonatal sheep.

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is partly due to impaired nitric oxide (NO)-cGMP signaling. BAY 41-2272 is a novel direct activator of soluble guanylate cyclase, but whether this drug may be an effective therapy for PPHN is unknown. We hypothesized that BAY 41-2272 would cause pulmonary vasodilation in a model of severe PPHN. To test this hypothesis, we compared the hemodynamic response of BAY 41-2272 to acetylcholine, an endothelium-dependent vasodilator, and sildenafil, a selective inhibitor of PDE5 in chronically instrumented fetal lambs at 1 and 5 days after partial ligation of the ductus arteriosus. After 9 days, we delivered the animals by cesarean section to measure their hemodynamic responses to inhaled NO (iNO), sildenafil, and BAY 41-2272 alone or combined with iNO. BAY 41-2272 caused marked pulmonary vasodilation, as characterized by a twofold increase in blood flow and a nearly 60% fall in PVR at day 1. Effectiveness of BAY 41-2272-induced pulmonary vasodilation increased during the development of pulmonary hypertension. Despite a similar effect at day 1, the pulmonary vasodilator response to BAY 41-2272 was greater than sildenafil at day 5. At birth, BAY 41-2272 dramatically reduced PVR and augmented the pulmonary vasodilation induced by iNO. We concluded that BAY 41-2272 causes potent pulmonary vasodilation in fetal and neonatal sheep with severe pulmonary hypertension. We speculate that BAY 41-2272 may provide a novel treatment for severe PPHN, especially in newborns with partial response to iNO therapy.

• Authors: Philippe Deruelle, Theresa R Grover, Steven H Abman
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 289 Issue 5 Pg. L798-806 (Nov 2005) ISSN: 1040-0605 [Print] United States
• PMID: 15964898 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
• Piperazines
• Purines
• Pyrazoles
• Pyridines
• Sulfones
• Nitric Oxide
• Sildenafil Citrate
• 3',5'-Cyclic-GMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Guanylate Cyclase
• Cyclic GMP
• Acetylcholine

Topics

• 3',5'-Cyclic-GMP Phosphodiesterases (antagonists & inhibitors)
• Acetylcholine (administration & dosage, pharmacology)
• Animals
• Animals, Newborn
• Cyclic GMP (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Female
• Fetus (drug effects, physiology)
• Guanylate Cyclase (metabolism)
• Hypertension, Pulmonary (etiology, physiopathology)
• Nitric Oxide (administration & dosage, metabolism, pharmacology)
• Piperazines (administration & dosage, pharmacology)
• Pregnancy
• Pulmonary Circulation (drug effects)
• Purines
• Pyrazoles (administration & dosage, pharmacology)
• Pyridines (administration & dosage, pharmacology)
• Sheep
• Signal Transduction (drug effects)
• Sildenafil Citrate
• Sulfones
• Vasodilation (drug effects)