ABSTRACT
PURPOSE: To examine a possible role for the angiotensin system in a rodent model of retinopathy of prematurity. METHODS: A previously described model was used in which oxygen cycling (5 days hyperoxia and 5 days hypoxia) induced retinal alterations in newborn mice. An angiotensin-converting enzyme inhibitor (perindopril), or angiotensin receptor antagonists AT1 (losartan) or AT2 (PD123319) were administered subcutaneously for 5 days after the hyperoxia exposure. According to histologic methods, the endothelial cell count within the anterior part of the ganglion cell layer was used for the evaluation of the compound effect. RESULTS: Histologic evaluation showed an increased number of endothelial cells in retinas of hypoxic pups compared with hyperoxic or normoxic pups. Hypoxic animals treated with perindopril (4 mg/kg) showed a significant decrease (29%, P < or = 0.001) in endothelial cell number (163 +/- 7) compared with hypoxic control animals (231 +/- 10). Losartan also decreased the endothelial cell number (14%, P < or = 0.05), whereas the AT2 antagonist had no effect. CONCLUSIONS: The data showed a protective effect of an angiotensin-converting enzyme inhibitor and of an AT1 receptor antagonist on hyperoxia- and normoxia-induced neovascularization in newborn mice. The results suggest a role for the angiotensin system in this model and that such compounds may be of interest in the prevention of proliferative retinopathies such as proliferative diabetic retinopathy.
Subject(s)
Angiotensin II/physiology , Hyperoxia/complications , Hypoxia/complications , Retinal Neovascularization/etiology , Retinopathy of Prematurity/etiology , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Animals, Newborn , Cell Count , Dextrans/metabolism , Endothelium , Fluoresceins/metabolism , Humans , Imidazoles/pharmacology , Infant, Newborn , Losartan/pharmacology , Mice , Mice, Inbred C57BL , Perindopril/pharmacology , Pyridines/pharmacology , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Receptors, Angiotensin/agonists , Renin-Angiotensin System/physiology , Retinal Ganglion Cells , Retinal Neovascularization/pathology , Retinal Neovascularization/prevention & control , Retinopathy of Prematurity/pathology , Retinopathy of Prematurity/prevention & controlABSTRACT
The effect of neutrophil elastase on the functional status of gelatinases was studied in an hamster model developed by intratracheal administration of lipopolysaccharide followed by in situ cell activation with phorbol myristate acetate. This resulted in the production in bronchoalveolar lavage fluids, in addition to the matrix metalloproteinase MMP-9, of a 75 kDa gelatinase associated with collagenolytic activity. Treatment in vivo with an elastase inhibitor abolished the latter activity. Since, in addition, elastase activates in vitro purified MMP-9 gelatinase into a similar 75 kDa entity, these data suggest that elastase may be a physiological activator of MMP-9 in vivo.
Subject(s)
Collagenases/metabolism , Leukocyte Elastase/metabolism , Lipopolysaccharides/toxicity , Lung/pathology , Animals , Bronchoalveolar Lavage Fluid , Cricetinae , Enzyme Activation , Gelatinases/metabolism , Lung/drug effects , Lung/physiopathology , Male , Matrix Metalloproteinase 9 , Mesocricetus , Substrate Specificity , Tetradecanoylphorbol Acetate/pharmacologyABSTRACT
The bronchodilating effect and other related pharmacological properties of an 8-amino alkyl substituted xanthine (S 9795) were compared with those of reference drugs, in particular theophylline. The in vitro studies using the tracheal ring, taenia coli, rat peritoneal mastocytes and enzymic preparations demonstrated the potency of S 9795 as an antiasthmatic drug, possessing protective activity superior to that of theophylline and enprofylline. S 9797 was 100 times more active as a cAMP phosphodiesterase inhibitor than theophylline. The compound also protected against mast cell degranulation and consequent release of spasmogen due to antigen-antibody reaction or induced by Ca2+ movements. Given orally or intravenously. S 9795 had a highly selective protective effect against bronchoconstriction induced by pharmacological reagents or allergic reactions with no demonstrable effect on the central nervous or cardiovascular systems. The pharmacological effects of S 9795 were of longer duration than those of theophylline and enprofylline. These studies demonstrate the potential therapeutic value of S 9795 in the therapy of bronchospastic disorders.
