A nitric oxide-releasing salbutamol elicits potent relaxant and anti-inflammatory activities.
Beta2-adrenoceptor agonists are widely used in the treatment of pulmonary diseases. We have investigated the relaxant and anti-inflammatory activities of NCX-950 (alpha'-[[(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 beta-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 microM 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 microM) also significantly reduced tumor necrosis factor-alpha, interleukin-6 (IL-6), transforming growth factor-beta, 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 microM) 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 beta2-adrenoceptor rather than the cGMP pathway.
Lagente
Vincent
V
Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Institut National de al Sante et de la Recherche Medicale, Université de Rennes 1, Rennes, France. vincent.lagente@univ-rennes1.fr
Naline
Emmanuel
E
Guenon
Isabelle
I
Corbel
Marianne
M
Boichot
Elisabeth
E
Burgaud
Jean-Luc
JL
Del Soldato
Piero
P
Advenier
Charles
C
D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018893:Bronchoalveolar Lavage; D001993:Bronchodilator Agents / Q000494:pharmacology; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones
D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D011433:Propranolol; D000068677:Sildenafil Citrate; D045726:Metalloproteases; D000420:Albuterol