Table 4.

An overview of potential therapeutic approaches for persistent pulmonary hypertension of the newborn (PPHN), studied in animal models or conceptual.

Treatment options	Mechanism of action	Animal model	Main results	Treatment protocol and relevant observations
Tadalafil	PDE5 inhibitor	◦Piglets, hypoxia-induced (51)	•Decreased PAP (by 54%) and increased cardiac output (by 88%) (p < 0.05) •Increased PaO2 (by 48 ± 21%) and decreased AaDO2 (by 74 ± 13%) (p < 0.01)	•Dose 1 mg/kg (single oral dose) •Higher selectivity for PDE5 and longer half-life
L-citrulline	Exogenous L-arginine (eNOS substrate)	◦Piglets, hypoxia-induced (52)	•Decreased PVR and decreased RV mass (p < 0.05) •Increased NO and decreased superoxide (eNOS recoupling) (p < 0.05)	•Dose: 1–1.5 g/day for 7 days (oral)
Riociguat	sGC stimulator	◦Lambs, ligated DA (53)	•Decreased PVR (by 60%) and increased PBF (by 2-fold) in lamb models (p < 0.01)	•BAY 41-2272: tool-compound for riociguat •Dose: 500 mcg (single infusion in LPA)
Cinaciguat	sGC activator	◦Lambs, ligated DA (54)	•Increased PBF (by 4-fold) and decreased PVR (by 80%) (p < 0.01)	•Dose: 150 mcg (single infusion in LPA) •Beneficial effects after oxidative stress
Selexipag	PGI2 receptor agonist	Conceptual	Based on concepts alone	•Oral administration •Promising results in adult PAH, with no apparent safety concerns (55)
Fasudil	ROCK inhibitor	◦Lambs, ligated DA (56)	•Increased PBF (by twofold) and decreased PVR (by 51 ± 11%) (p < 0.05)	•Dose: 500 mcg (single infusion in LPA)
		◦Rats, hypoxia-induced (57)	•Decreased PVR (p < 0.05)	•Dose: 30 mg/kg (single IV bolus) •Severe adverse effects(systemic hypotension, growth restriction) (58)
Simvastatin	RhoA (and ROCK) inhibitor	◦Rats, hypoxia-induced (59)	•Decreased PVR (either preventive or rescue therapy) (p < 0.05) •Decreased RV mass (either preventive or rescue therapy) (p < 0.05) •Improved exercise capacity and decreased pulmonary arterial remodeling (if rescue therapy) (p < 0.05)	•Dose: 2 mg/kg/day for either 7 (rescue) or 14 (preventive) days (intraperitoneal injection) •No systemic hypotension or apparent toxic effects on skeletal muscle, liver, or brain
Rosiglitazone	PPAR-γ agonist	◦Lambs, ligated DA (60)	•Decreased in vitro proliferation of PASMCs (by 51%) (p < 0.01)	•Prevents the development of PAH induced by hypoxia (61) or hyperoxia (62) in rats
Sapropterin	Exogenous BH4 (eNOS cofactor)	◦Piglets, hypoxia-induced (63)	•Decreased PVR, decreased PAP, and decreased RV mass (p < 0.05) •Increased NO and decreased superoxide (eNOS recoupling) (p < 0.05)	•Dose: 20 mg/kg for 1 day, followed by 40 mg/kg/day for 7 days (oral) •Established safety profile in human infants (64)
rhSOD	Exogenous SOD	◦Lambs, ligated DA (65, 66)	•Improved a/A ratio, improved OI and improved PaO2 (p < 0.05) •Oxygenation improved more rapidly if rhSOD + iNO, compared with either intervention alone (p < 0.05)	•Dose: 5 mg/kg (single endotracheal dose) •rhSOD also reduced pulmonary arterial contractility (isolated vessel) and oxidation
			•Decreased PAP (p < 0.05) •Decreased PVR if rhSOD + iNO, compared with either intervention alone (p < 0.05)	•Dose: 5 mg/kg (single endotracheal dose) •No systemic hypotension
ω-3 LC-PUFAs	Antioxidant Anti-inflammatory	◦Lambs (no PPHN) (67)	•Increased PBF (by 30%) and decreased PVR (by 28%) (p < 0.0001)	•Dose (Omegaven®): 2.4 ml (single infusion in LPA)
Ketanserin	5-HT2A antagonist	◦Lambs, ligated DA (68)	•Decreased PAP, decreased PVR (by 26%), and increased PBF (by 27%) (p < 0.05)	•Dose: 20 mg (single infusion in LPA) •Systemic hypotension when used for adult PAH (69)
Sarpogrelate	5-HT2A antagonist	Conceptual	Based on concepts alone	•Oral administration •No systemic hypotension (in human adults)
rhVEGF	Exogenous VEGF	◦Lambs, ligated DA (70)	•Decreased PAP (p < 0.05) •Increased expression of lung eNOS (p < 0.05) and decreased pulmonary artery wall thickness (by 34%) (p < 0.01)	•Dose: 15 mcg/day for 14 days (infusion in LPA)

Only statistically significant results are presented. ω-3 LC-PUFAs, ω-3 long-chain polyunsaturated fatty acids; 5-HT2A, 5-HT receptor 2A; BH4, tetrahydrobiopterin; a/A, arteriolar-to-alveolar oxygen ratio; AaDO₂, alveolar–arterial oxygen difference; DA, ductus arteriosus; eNOS, endothelial NO synthase; iNO, inhaled nitric oxide; IV, intravenous; LPA, left pulmonary artery; OI, oxygenation index; PaO₂, arterial partial pressure of oxygen; PAP, pulmonary artery pressure; PBF, pulmonary blood flow; PAH, pulmonary arterial hypertension; PPAR-γ, peroxisome proliferator-activated receptor-γ; PVR, pulmonary vascular resistance; PDE5, phosphodiesterase 5; PGI2, prostacyclin; RhoA, Ras homologue family member A; ROCK, Rho-kinase; rhSOD, recombinant superoxide dismutase; rhVEGF, recombinant vascular endothelial growth factor; ROCK, Rho-kinase; RV, right ventricle; sGC, soluble guanylyl cyclase.