verlukast and Hypertension--Pulmonary

Cyclic nucleotides (e.g., cAMP and cGMP) are ubiquitous second messengers that affect multiple cell functions including vascular tone and vascular cell proliferation. After production, different processes can regulate the concentration of cyclic nucleotides. Cyclic nucleotides' degradation by phosphodiesterase (PDE) enzymes has well-known roles in regulating cyclic nucleotides concentrations. Recently, recognition of ATP-binding cassette (ABC) transporter contribution to both local and global regulation of cAMP has been acknowledged. Recent data support an important role of cyclic nucleotide efflux in the pathobiology of pulmonary hypertension, thus suggesting that inhibition of cyclic nucleotide efflux proteins might be a useful strategy to prevent and treat PH.

Topics: Animals; Cyclic AMP; Cyclic GMP; Humans; Hypertension, Pulmonary; Multidrug Resistance-Associated Proteins; Propionates; Quinolines; Signal Transduction

Multidrug resistance-associated protein 4 (MRP4, also known as Abcc4) regulates intracellular levels of cAMP and cGMP in arterial SMCs. Here, we report our studies of the role of MRP4 in the development and progression of pulmonary arterial hypertension (PAH), a severe vascular disease characterized by chronically elevated pulmonary artery pressure and accompanied by remodeling of the small pulmonary arteries as a prelude to right heart failure and premature death. MRP4 expression was increased in pulmonary arteries from patients with idiopathic PAH as well as in WT mice exposed to hypoxic conditions. Consistent with a pathogenic role for MRP4 in PAH, WT mice exposed to hypoxia for 3 weeks showed reversal of hypoxic pulmonary hypertension (PH) following oral administration of the MRP4 inhibitor MK571, and Mrp4-/- mice were protected from hypoxic PH. Inhibition of MRP4 in vitro was accompanied by increased intracellular cAMP and cGMP levels and PKA and PKG activities, implicating cyclic nucleotide-related signaling pathways in the mechanism underlying the protective effects of MRP4 inhibition. Our data suggest that MRP4 could represent a potential target for therapeutic intervention in PAH.

Topics: Animals; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Enzyme Inhibitors; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Hypoxia; Leukotriene Antagonists; Lung; Mice; Mice, Knockout; Multidrug Resistance-Associated Proteins; Muscle, Smooth, Vascular; Propionates; Pulmonary Artery; Quinolines; RNA Interference; Vasoconstriction; Vasodilation