Inhibition of phosphodiesterase 2 augments cGMP and cAMP signaling to ameliorate pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right ventricular failure. Loss of endothelium-derived nitric oxide (NO) and prostacyclin contributes to PH pathogenesis, and current therapies are targeted to restore these pathways. Phosphodiesterases (PDEs) are a family of enzymes that break down cGMP and cAMP, which underpin the bioactivity of NO and prostacyclin. PDE5 inhibitors (eg, sildenafil) are licensed for PH, but a role for PDE2 in lung physiology and disease has yet to be established. Herein, we investigated whether PDE2 inhibition modulates pulmonary cyclic nucleotide signaling and ameliorates experimental PH. METHODS AND RESULTS: The selective PDE2 inhibitor BAY 60-7550 augmented atrial natriuretic peptide- and treprostinil-evoked pulmonary vascular relaxation in isolated arteries from chronically hypoxic rats. BAY 60-7550 prevented the onset of both hypoxia- and bleomycin-induced PH and produced a significantly greater reduction in disease severity when given in combination with a neutral endopeptidase inhibitor (enhances endogenous natriuretic peptides), trepostinil, inorganic nitrate (NO donor), or a PDE5 inhibitor. Proliferation of pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension was reduced by BAY 60-7550, an effect further enhanced in the presence of atrial natriuretic peptide, NO, and treprostinil. CONCLUSIONS: PDE2 inhibition elicits pulmonary dilation, prevents pulmonary vascular remodeling, and reduces the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile is dependent on natriuretic peptide bioactivity and is additive with prostacyclin analogues, PDE5 inhibitor, and NO. PDE2 inhibition represents a viable, orally active therapy for PH.

The effects of racemic albuterol versus levalbuterol in very low birth weight infants.

Bronchodilators have been used in premature infants. Levalbuterol (LEV) an R-isomer of Albuterol has fewer hemodynamic side effects than Racemic Albuterol (RAC) in adults and children. In a retrospective study we sought to investigate the effects of LEV (0.31 mg) versus RAC (1.25 mg) in very low-birth weight infants (VLBW) who were treated with a beta-2 agonist for > or =2 weeks. Medical records (between January 2001 and December 2006) were reviewed for patients' demographics, medications use, hemodynamic and respiratory parameters, hypokalemia and hyperglycemia. Among 811 VLBW infants who were admitted to our NICU, 16 infants received RAC and 31 infants received LEV for > or =2 weeks. Infants who received RAC were younger, smaller, and received less Ipratropium Bromide (IB) than infants who received LEV [26.1 +/- 1.2 weeks vs. 28.1 +/- 3.7 weeks (P = 0.01), 817 +/- 211 g vs. 1,127 +/- 589 g (P = 0.01) and 2/16 (12%) vs. 15/31 (48%; P = 0.01); respectively]. In infants treated exclusively with RAC or LEV without IB, mean arterial blood pressures were lower in the RAC (n = 14) than the LEV group (n = 16, P = 0.05 by general linear model with repeated measures); however there were no differences in daily heart rates, oxygen supplementations, oxygen saturations, or respiratory rates. Also there were no differences between the two groups in hypokalemia or hyperglycemia. We conclude that LEV at a dose of 0.31 mg might have an indication in VLBW infants who are at risk for hemodynamic instability.