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|Tutti gli autori / Collaboratori:||
Olivier Pauvert; Jean-Pierre Savineau; Université de Bordeaux II.
|Note:||Thèse : 2001BOR28919.|
|Descrizione:||227 p. ; 30 cm.|
|Responsabilità:||Olivier Pauvert ; Sous la dir. de Jean-Pierre Savineau.|
Pulmonary artery tone is controlled by several factors including as nitric oxide and cyclic nucleotides (cAMP and cGMP). Molecular and cellular mechanisms involved in the action of NO and cyclic nucleotides are not fully elucidated. Moreover, these mechanisms could be altered by chronic hypoxia which leads to the development of pulmonary artery hypertension (PAHT). The aim of the present study was to characterise, in vitro, the effects of NO and cyclic nucleotides of the pulmonary artery reactivity and calcium signalling in pulmonary vascular smooth muscle which is the main event of the contraction. Experiments were performed on rat and bovine pulmonary arteries and on freshly isolated pulmonary artery myocytes. Our results show that : 1. NO, cAMP and cGMP inhibit agonist-induced calcium oscillations by impairing the inositol 1, 4, 5 triphosphate (IP3) pathway. This action accounts for the relaxant effect of these compounds. In arteries from normoxic rats, NO-induced relaxation is cGMP-dependent and PKG-independent, whereas in arteeries from chronic hypoxia rats a cGMP-independent component related to the inhibition of 20-HETE synthesis by NO appears. 2. 20-HETE directly alters electrophysiological properties of calcium-activated potassium channels (Kca by ddcreasing the channel opening probability in purified and reconstituted Kca. 3. Pharmacological characterisation of cyclic nucleotide-dependent phosphodiesterases (PDE) reveals the presence, in the media of pulmonary arteries, at least, 5 isoenzymes the main of which are PDE3, 4 and 5. The inhibition of PDE also induced vasorelaxation. In particularly, sildenafil inhibits hydrolytic activity of the partially purified PDE5 (IC50 = 3.4 nM) and the phenylephrine-induced contraction (IC50 = 30 nM). In conclusion, our study shows that NO and cyclic nucleotides are potent pulmonary artery relaxants. Cellular and molecular mechanisms underlying this action are altered by chronic hypoxia. Combination of NO donors with PDE inhibitors could be relevant for the pharmacological treatment of PAHT.
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