Abstract
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.
Footnotes
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This study was supported by NicOx and INSERM and has been presented at the 6th World Congress on Inflammation at Vancouver (Canada) and published as an abstract [Inflammation Research, 2003;52:S109].
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DOI: 10.1124/jpet.103.061739.
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ABBREVIATIONS: COPD, chronic obstructive pulmonary disease; NO, nitric oxide; NOS, nitric-oxide synthase; NCX-950, α′-[[(1,1-dimethylethy)amino]methyl]-4-hydroxy-1,3-benzenedimethanol nitrate; 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; LPS, lipopolysaccharide; ODQ, 1H-[1,2,4]oxadiazolo[4,3-]quinolaxin-1-one; TGF, transforming growth factor; BAL, bronchoalveolar lavage; TNF, tumor necrosis factor; IL, interleukin; TBS, Tris-buffered saline; GEA 3175, 1,2,3,4-oxatriazolium-3-(3-chloro-2-methylphenyl)-5-[[(4-methylphenyl)sulfonyl]amino], hydroxide inner salt.
- Received October 20, 2003.
- Accepted April 8, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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