title: Alteration of vascular reactivity in heart failure: role of phosphodiesterases 3 and 4.
abstract: OBJECTIVE
  This study examined the role of the main vascular cAMP-hydrolysing phosphodiesterases (cAMP-PDE) in the regulation of basal vascular tone and relaxation of rat aorta mediated by β-adrenoceptors, following heart failure (HF).
  
  
  METHODS
  Twenty-two weeks after proximal aortic stenosis, to induce HF, or SHAM surgery in rats, we evaluated the expression, activity and function of cAMP-PDE in the descending thoracic aorta.
  
  
  RESULTS
  HF rat aortas exhibited signs of endothelial dysfunction, with alterations of the NO pathway, and alteration of PDE3 and PDE4 subtype expression, without changing total aortic cAMP-hydrolytic activity and PDE1, PDE3 and PDE4 activities. Vascular reactivity experiments using PDE inhibitors showed that PDE3 and PDE4 controlled the level of PGF2α -stimulated contraction in SHAM aorta. PDE3 function was partially inhibited by endothelial NO, whereas PDE4 function required a functional endothelium and was under the negative control of PDE3. In HF, PDE3 function was preserved, but its regulation by endothelial NO was altered. PDE4 function was abolished and restored by PDE3 inhibition. In PGF2α -precontracted arteries, β-adrenoceptor stimulation-induced relaxation in SHAM aorta, which was abolished in the absence of functional endothelium, as well as in HF aortas, but restored after PDE3 inhibition in all unresponsive arteries.
  
  
  CONCLUSIONS
  Our study underlines the key role of the endothelium in controlling the contribution of smooth muscle PDE to contractile function. In HF, endothelial dysfunction had a major effect on PDE3 function and PDE3 inhibition restored a functional relaxation to β-adrenoceptor stimulation.
authors.affiliation: Faculté de Pharmacie, Inserm UMR-S 769, LabEx LERMIT-DHU TORINO, Châtenay-Malabry, France; Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Hubert
authors.forename: M
authors.initials: M
authors.lastname: Belacel-Ouari
authors.forename: B
authors.initials: B
authors.lastname: Manoury
authors.forename: K
authors.initials: K
authors.lastname: Zhai
authors.forename: V
authors.initials: V
authors.lastname: Domergue-Dupont
authors.forename: P
authors.initials: P
authors.lastname: Mateo
authors.forename: F
authors.initials: F
authors.lastname: Joubert
authors.forename: R
authors.initials: R
authors.lastname: Fischmeister
authors.forename: V
authors.initials: V
authors.lastname: Leblais
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics / Q000502:physiology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000502:physiology*; D015237:Dinoprost / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D015363:Quinolones; D012333:RNA, Messenger; C021294:cilostamide; D015237:Dinoprost; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007545:Isoproterenol