Lagente Vincent, Naline Emmanuel, Guenon Isabelle, Corbel Marianne, Boichot Elisabeth, Burgaud Jean-Luc, Del Soldato Piero, Advenier Charles
Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Institut National de al Sante et de la Recherche Medicale, Université de Rennes 1, Rennes, France.
J Pharmacol Exp Ther. 2004 Jul;310(1):367-75. doi: 10.1124/jpet.103.061739. Epub 2004 Apr 14.
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.
β2肾上腺素能受体激动剂广泛应用于肺部疾病的治疗。我们研究了NCX - 950（α'-[[(1,1 - 二甲基乙基)氨基]甲基]-4 - 羟基 - 1,3 - 苯二甲醇硝酸盐）（一种释放一氧化氮的沙丁胺醇）对人离体支气管的舒张作用以及对小鼠脂多糖（LPS）诱导的急性气道炎症的影响。NCX - 950（10⁻⁸ - 10⁻⁵ M）引起人离体支气管舒张的程度略高于沙丁胺醇，β肾上腺素能阻断药普萘洛尔可减弱这种舒张作用，但鸟苷酸环化酶抑制剂ODQ（1H - [1,2,4]恶二唑并[4,3 - a]喹喔啉 - 1 - 酮）则无此作用。用NCX - 950（1、10和100 μM气雾剂）处理小鼠，可显著抑制LPS气雾剂诱导的支气管肺泡灌洗（BAL）液中的中性粒细胞流入，而等摩尔剂量的沙丁胺醇仅有中度抑制作用。用NCX - 950（100 μM）预处理小鼠，也可显著降低BAL液中肿瘤坏死因子 - α、白细胞介素 - 6（IL - 6）、转化生长因子 - β和基质金属蛋白酶 - 9的释放，而沙丁胺醇则无此效果。普萘洛尔而非ODQ可抑制NCX - 950对BAL液中中性粒细胞流入和IL - 6释放的抑制活性。一种释放一氧化氮的西地那非NCX - 911 [（5 - [2 - 乙氧基 - 5 - (4 - 甲基哌啶基磺酰基)phenyl]-1 - 甲基 - 3 - 正丙基 - 1,6 - 二氢 - 7H - 吡唑并[4,3 - d]嘧啶 - 7 - one硝酸盐）]，而非西地那非（100 μM），也可减少LPS暴露后小鼠的中性粒细胞流入。本研究报道，与沙丁胺醇相比，NCX - 950具有更强的舒张和抗炎活性，这些作用可能主要归因于β2肾上腺素能受体的激活而非cGMP途径。
