Selective type 5 phosphodiesterase inhibition alters pulmonary hemodynamics and lung liquid production in near-term fetal lambs

Abstract

Nitric oxide causes dilation of the pulmonary circulation and reduction in net lung liquid production in the fetal lamb, two critical perinatal events. Phosphodiesterase inhibition alone causes similar changes and also enhances the effects of nitric oxide. To better define the cyclic guanosine 5'-monophosphate (GMP) pathway in these events, we studied the effects of a specific phosphodiesterase inhibitor, E4021, on pulmonary arteries and veins isolated from near-term fetal lambs, as well as in intact, chronically instrumented late-gestation fetal lambs. In the in vitro experiments, both pulmonary arteries and veins relaxed to E4021 in a dose-dependent manner, although pulmonary veins were significantly more sensitive to E4021. Pretreatment with N(G)-nitro-l-arginine (L-NNA) abolished this response in arteries but not in veins. In both arteries and veins, pretreatment with beta-phenyl-1,N2-etheno-8-bromoguanosine-3',5'-cyclic monophosphorothionate blunted relaxations to E4021. In the in vivo experiments, E4021 infusion into either the pulmonary artery or central venous circulation increased pulmonary blood flow and decreased pulmonary vascular resistance, and these responses were blunted by pretreatment with L-NNA. Net lung liquid production, measured by a dye-dilution technique using blue dextran, decreased when E4021 was infused directly into the pulmonary artery and this effect was not altered by L-NNA. There was no effect on lung liquid production when E4021 was infused into the central venous circulation. Taken together, these results suggest that the pulmonary hemodynamic effects of E4021 involve the cyclic GMP pathway and are primarily nitric oxide synthase dependent. In contrast, the effects on E4021 on net lung liquid production appear to be independent of nitric oxide synthase, suggesting that these two critical perinatal events might be modulated independently.

Role of Pulmonary Artery Reactivity and Nitric Oxide in Injury and Inflammation Following Lung Contusion

“…Inhibition of phosphodiesterase 5 enzymes by the specific inhibitor, E4021 resulted in concentration-dependent relaxation of PA isolated from rats (80 ± 7% relaxation with 10 −6 M) similar to our previous studies in lambs (21, 22). There was no significant difference in relaxation between control and post-contusion PA (87 ±11%).…”

Phosphodiesterases: Emerging Therapeutic Targets for Neonatal Pulmonary Hypertension

“…In those seven, dipyridamole attenuated the rise in pulmonary pressure after acute withdrawal of iNO (Ivy et al 1998). None of these case reports described a significant decrease in systemic blood pressure similar to that observed in the PPHN lamb model (Dukarm et al 2005). …”

Gene identification and analysis of transcripts differentially regulated in fracture healing by EST sequencing in the domestic sheep

“…The accumulation of genome-wide sequence data for model organisms is of obvious benefit for many kinds of scientific analysis. Although the sheep is of great economic importance and has been used as a model organism to study such diverse topics as fracture healing [ 1 ], ovarian function [ 2 ], hypernatremic hypertension [ 3 ], and pulmonary function [ 4 ], relatively little sequence information is available for this organism, and DNA sequences are available for only a small number of sheep genes.…”