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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 14, 2004; DOI: 10.1124/jpet.103.061739

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*NITRIC OXIDE
*PROPRANOLOL HYDROCHLORIDE


Received for publication October 20, 2003.
Revised April 7, 2004.
Accepted for publication April 8, 2004.

A nitric oxide-releasing salbutamol, elicits potent relaxant and anti-inflammatory activities

Vincent Lagente 1*, Emmanuel Naline 2, Isabelle Guenon 3, Marianne Corbel 3, Elisabeth Boichot 3, Jean-Luc Burgaud 4, Piero Del Soldato 4, Charles Advenier 5

1 INSERM U620, Universite de Rennes 1 2 UPRES EA220-Pharmacologie, UFR Biomedicale des Saints Peres. 75270 Paris cedex, France 3 INSERM U620, Universite de Rennes 1, 35043 Rennes cedex, France 4 Nicox SA, 06906 Sophia-Antipolis cedex, France 5 UPRES EA220-Pharmacologie, UFR Biomedicale des Saints Peres, 75270 Paris cedex, France

* Address correspondence to: E-mail: vincent.lagente{at}rennes.inserm.fr

Abstract

{beta}2-adrenoceptor agonists are widely used in the treatment of pulmonary diseases. We have investigated the relaxant and the anti-inflammatory activities of NCX-950 (a nitric oxide-releasing salbutamol) in human isolated bronchi and on 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 µM, aerosol) markedly inhibited the neutrophil influx induced by LPS aerosol in BAL fluid, whereas salbutamol, at equimolar doses, elicited a moderate inhibition. Pretreatment of mice with NCX-950 (100 µM) also significantly reduced TNF- {alpha}, IL-6, TGF-{beta} and MMP-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 NO-sildenafil (NCX-911), 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 in comparison to salbutamol and these effects may be mainly due to the activation of b2-adrenoceptor rather than cGMP pathway.


Key words: NO-salbutamol, NO-sildenafil, airway inflammation, bronchodilatation, cytokine, nitric oxide


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B. J. Proskocil and A. D. Fryer
{beta}2-Agonist and Anticholinergic Drugs in the Treatment of Lung Disease
Proceedings of the ATS, November 1, 2005; 2(4): 305 - 310.
[Abstract] [Full Text] [PDF]


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