PT  - JOURNAL ARTICLE
AU  - Vincent Lagente
AU  - Emmanuel Naline
AU  - Isabelle Guenon
AU  - Marianne Corbel
AU  - Elisabeth Boichot
AU  - Jean-Luc Burgaud
AU  - Piero Del Soldato
AU  - Charles Advenier
TI  - A Nitric Oxide-Releasing Salbutamol Elicits Potent Relaxant and Anti-Inflammatory Activities
AID  - 10.1124/jpet.103.061739
DP  - 2004 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 367--375
VI  - 310
IP  - 1
4099  - http://jpet.aspetjournals.org/content/310/1/367.short
4100  - http://jpet.aspetjournals.org/content/310/1/367.full
SO  - J Pharmacol Exp Ther2004 Jul 01; 310
AB  - β2-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 (1H-[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-7H-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 β2-adrenoceptor rather than the cGMP pathway. The American Society for Pharmacology and Experimental Therapeutics