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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Institut National de la Sante et de la Recherche Medicale, Université de Rennes 1, Rennes, France (V.L., I.G., M.C., E.B.); UPRES EA220-Pharmacologie, U.F.R. Biomédicale des Saints-Pères, Paris, France (E.N., C.A.); NicOx S.A., Sophia-Antipolis, France (J.L.B., P.D.S.)

₂-Adrenoceptor agonists are widely used in the treatment of pulmonary diseases. We have investigated the relaxant and anti-inflammatory activities of NCX-950 ('-[[(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 -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-, interleukin-6 (IL-6), transforming growth factor-, 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 ₂-adrenoceptor rather than the cGMP pathway.

Address correspondence to: Prof. Vincent Lagente, Faculté de Pharmacie, Université de Rennes 1, 2, avenue du Professeur Léon Bernard, 35043 Rennes cedex, France. E-mail: vincent.lagente{at}univ-rennes1.fr

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