85 There are 11 isoforms of phosphodiesterases (PDEs). The most important are the PDE3 and PDE5, which preferentially degrade cAMP and cGMP, respectively. Sildenafil produces vasodilation by inhibiting PDE5. Dipyridamole, zaprinast, and pentoxifylline are PDE5 inhibitors that are seldom used, as they have important systemic effects. Studies in neonates with pulmonary hypertension

have shown that sildenafil selectively reduces pulmonary vascular resistance with few systemic effects.86, 87, 88 and 89 Its effect on pulmonary vasculature appears to be independent from the underlying cause, and thus effective in idiopathic pulmonary hypertension associated with heart conditions, lung disease, and PPHN.90 In the postoperative period of heart disease, sildenafil decreased pulmonary artery pressure and prevented rebound after Osimertinib research buy withdrawal

of NO.91 In a Cochrane meta-analysis with 37 newborns from centers that lacked NO and high frequency ventilation, significant improvement in oxygenation was observed in the group receiving sildenafil.92 Sildenafil is safe, effective, and easily administered. As discussed earlier, its vasodilator effect extends to poorly ventilated JNK inhibitor price areas in the lungs, which changes the ventilation/perfusion ratio, increases the intrapulmonary shunt, and worsens oxygenation. In an animal model of neonatal lobar atelectasis, sildenafil inhibited pulmonary vasoconstriction in response to hypoxia and worsened oxygenation.58 Using tadalafil, another PDE5 inhibitor in the same animal model without lobar atelectasis, a decrease in Masitinib (AB1010) pulmonary vascular resistance and improved oxygenation were demonstrated.93 Milrinone causes pulmonary vasodilation by inhibiting PDE3. Originally used to reduce the afterload and as an inotropic agent, it also has been shown to be effective in the treatment of neonatal pulmonary hypertension. Recently, Lakshminrusimha et al. demonstrated, in an animal model of PPHN, that pretreatment with milrinone increased the effect of prostaglandin in pulmonary artery relaxation.94

This would explain the findings of Bassller and MacNamara, who, when studying four and nine newborns, respectively, demonstrated a significant improvement in oxygenation with the use of milrinone after unsatisfactory response to iNO.95 and 96 In adults, the use of bosentan, a nonspecific antagonist of receptors A and B, significantly improves symptoms and exercise capacity in patients with pulmonary hypertension. In newborns, the plasma levels of ET1 are high, with a linear correlation with disease severity.97 These data have stimulated the use and publication of some case reports with the use of bosentan in neonates with PPHN.98 and 99 The usefulness of these agents in the treatment of PPHN still requires further clinical investigation before it can be recommended. Other drugs have been tested in animal models with promising effects.