A Nitric Oxide-Releasing Salbutamol Elicits Potent Relaxant and Anti-Inflammatory Activities

• Published in: The Journal of pharmacology and experimental therapeutics 2004-07, Vol.310 (1), p.367-375
• Main Authors: Lagente, Vincent, Naline, Emmanuel, Guenon, Isabelle, Corbel, Marianne, Boichot, Elisabeth, Burgaud, Jean-Luc, Del Soldato, Piero, Advenier, Charles
• Format: Article
• Language: English
• Subjects: Albuterol - pharmacology; Animals; Anti-Inflammatory Agents - pharmacology; Bronchoalveolar Lavage; Bronchodilator Agents - pharmacology; Cell Movement; Cytokines - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Humans; Interleukin-6 - metabolism; Lipopolysaccharides - pharmacology; Male; Metalloproteases - metabolism; Mice; Mice, Inbred BALB C; Nitric Oxide - physiology; Nitric Oxide Donors - pharmacology; Piperazines - pharmacology; Propranolol - pharmacology; Pulmonary Disease, Chronic Obstructive - chemically induced; Purines; Sildenafil Citrate; Sulfones
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.061739

β 2 -Adrenoceptor agonists are widely used in the treatment of pulmonary diseases. We have investigated the relaxant and anti-inflammatory activities of NCX-950 (α′-[[(1,1-dimethylethy)amino]methyl]-4-hydroxy-1,3-benzenedimethanol nitrate) (a nitric oxide-releasing salbutamol) in human isolated bronchi and on lipopolysaccharide (LPS)-induced acute airway inflammation in mice. NCX-950 (10 -8 -10 -5 M) elicited a relaxation of human isolated bronchi moderately higher than salbutamol, which was reduced by a β-adrenergic blocking drug, propranolol, but not by an inhibitor of guanylate cyclase, ODQ (1 H -[1,2,4]oxadiazolo[4,3-] quinolaxin-1-one). The treatment of mice with NCX-950 (1, 10, and 100 μM aerosol) markedly inhibited the neutrophil influx induced by LPS aerosol in bronchoalveolar lavage (BAL) fluid, whereas salbutamol at equimolar doses elicited a moderate inhibition. Pretreatment of mice with NCX-950 (100 μM) also significantly reduced tumor necrosis factor-α, interleukin-6 (IL-6), transforming growth factor-β, and matrix metalloproteinase-9 release in BAL fluid, whereas salbutamol was ineffective. Propranolol, but not ODQ, suppressed the inhibitory activity of NCX-950 on neutrophil influx and IL-6 release in BAL fluids. A nitric oxide-releasing sildenafil NCX-911 [(5-[2-ethoxy-5-(4-methylpiperidinylsulfonyl)phenyl]-1-methyl-3- n -propyl-1,6-dihydro-7 H -pyrazolo[4,3- d ]pyrimidin-7-one nitrate)], but not sildenafil (100 μM) also reduced the neutrophil influx following LPS exposure in mice. This study reported that NCX-950 elicits potent relaxant and anti-inflammatory activities compared with salbutamol, and these effects may be mainly due to the activation of the β 2 -adrenoceptor rather than the cGMP pathway.