NO stimulates soluble guanylate cyclase to produce the vasodilator cGMP, which is cleared by PDE5 in the lung. We studied the effects of E4021, a highly specific and potent PDE5 inhibitor, alone and in combination with inhaled NO in a lamb model of PPHN. Fetal lambs underwent ductal ligation 9 days prior to delivery. At delivery, lambs were instrumented for measurement of PA pressure (PAP), pulmonary blood flow (Qp), left atrial pressure, and aortic pressure. We measured pulmonary and systemic vascular responses to 20 minute infusions of E4021 at 10μg/kg/min alone and in combination with 0.5 and 5 ppm NO. For comparison, two groups received 0.5 and 5 ppm NO alone. PAP decreased and Qp increased significantly in all groups except the 0.5 ppm NO group. PVR and oxygenation data are shown in the table (* p < 0.05 vs baseline by ANOVA, ** p < 0.05 vs baseline by Wilcoxon signed rank test). Aortic pressure did not decrease more than 10% in any group. We conclude E4021 alone improves pulmonary hemodynamics and oxygenation in newborn lambs with PPHN. The vascular effects of E4021 are not augmented following inhalation of a subthreshold (0.5 ppm) or threshold (5 ppm) concentration of NO. We speculate that this lack of augmentation may be because the improvement in pulmonary hemodynamics following E4021 alone is equivalent to 50-100 ppm NO in this model (J Pediatr 1993;122:743).

Table 1 No caption available.
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