NO-steroids: potent anti-inflammatory drugs with bronchodilating activity in vitro.
The synthesis of nitric oxide (NO) releasing anti-inflammatory molecules is an innovative strategy to design novel anti-inflammatory drugs. These compounds slowly release NO, via an enzymatic pathway conferring new biological activities. Here we report the potent anti-inflammatory profile and the bronchodilator effect of nitro-derivatives of steroids, prednisolone, especially. The experiments were performed on guinea pig trachea or perfused bronchioles precontracted by methacholine. We demonstrated for the first time that unlike the parent compounds which produced weak bronchodilation at the maximum used dose (10(-4) M), NO-steroids caused a significant bronchodilating activity up to 70% of the maximal relaxation induced by 10(-4) M papaverine. This effect was epithelium- and endogenous-independent but cGMP-dependent. Taken together these data suggest that NO-steroids possessed a more potent anti-inflammatory activity than native compounds coupled with a concentration-dependent bronchodilating activity. Further studies are required to determine if NO-steroids will be effective as anti-inflammatory agents in the clinic.
Tallet
Dominique
D
Laboratoire de Pharmacologie, Faculté de Pharmacie de Limoges, 2 rue du Docteur Marcland, 87025 Limoges cedex, France.
Del Soldato
Piero
P
Oudart
Nicole
N
Burgaud
Jean-Luc
JL
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D007249:Inflammation / Q000188:drug therapy; D016210:Methacholine Chloride / Q000494:pharmacology; D008956:Models, Chemical; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009924:Organ Culture Techniques; D010208:Papaverine / Q000494:pharmacology; D010477:Perfusion; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011239:Prednisolone / Q000494:pharmacology; D013256:Steroids / Q000138:chemical synthesis / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D013256:Steroids; D014665:Vasodilator Agents; D016210:Methacholine Chloride; D009569:Nitric Oxide; D003907:Dexamethasone; D011239:Prednisolone; D010208:Papaverine; D019331:NG-Nitroarginine Methyl Ester