NO stimulates soluble guanylate cyclase to produce the vasodilator cGMP which is cleared by PDE5 in the lung. We studied the effects of E4021, which has been reported to be a potent inhibitor for PDE5. We used a lamb model of PPHN in which the ductus arteriosus is ligated in the late gestation fetus 9-10 days prior to delivery. This model has been shown to have decreased NO synthase content and activity. In the first protocol, fifth generation pulmonary arteries (PA), veins (PV), and mesenteric arteries were isolated from PPHN lambs (n=4) and age matched controls (n=5), and studied using standard tissue bath techniques. Concentration response curves to 10-8 to 10-5 M E4021 were performed in vessels constricted with an submaximal dose of norepinephrine and pretreated with indomethacin. E4021 dilated mesenteric arteries by 46 ± 11% at 10-5 M, a response which was completely blocked by LNA. E4021 dilated PA from control lambs by 38± 9%, but had no effect on hypertensive PA's even at the highest concentration. In PV from both control and hypertensive lambs, E4021 produced complete dilation at 10-7 M. LNA did not inhibit this effect. In the second protocol, intact lambs were fully instrumented for measurement of PA pressure, pulmonary blood flow (QP), left atrial pressure, and aortic pressure(AoP). We measured pulmonary and systemic vascular responses to 30 minute infusions of E4021 at 1, 10, and 100 μg/kg/min in random order. Values are expressed as a percent of baseline. (* p<0.05 by ANOVA vs baseline)Table

Table 1
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We conclude that E4021 dilates isolated PV and systemic vessels from PPHN lambs. In PV, the effect appears independent of endothelial NO synthesis. In intact lambs with PPHN, E4021 dilates the pulmonary circulation more prominantly than the systemic circulation. Our findings in the isolated PV would lead us to speculate that the effect in the pulmonary circulation is independent of NO.

Funded by NIH HL #54705, AHA, and WCRF of Buffalo