title: Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats.
abstract: Sildenafil, a potent type 5 nucleotide-dependent phosphodiesterase (PDE) inhibitor, has been recently proposed as a therapeutic tool to treat or prevent pulmonary artery hypertension (PAHT). We thus studied the effect of sildenafil on both the calcium signaling of isolated pulmonary artery smooth muscle cells (PASMCs) and the reactivity of pulmonary artery (PA) obtained from chronic hypoxia (CH)-induced pulmonary hypertensive rats compared with control (normoxic) rats. CH rats were maintained in an hypobaric chamber (50.5 kPa) for 3 wk leading to full development of PAHT. Intracellular calcium concentration ([Ca2+]i) was measured in PASMCs loaded with the calcium fluorophore indo 1. Unlike in control rats, sildenafil (10-100 nM) decreased the resting [Ca2+]i value in PASMCs obtained from CH rats. In PASMCs from both control and CH rats, sildenafil concentration dependently inhibited the [Ca2+]i response induced by G-coupled membrane receptor agonists such as angiotensin II and phenylephrine but had no effect on the amplitude of the [Ca2+]i response induced by caffeine. Sildenafil (0.1 nM-1 microM) concentration dependently reduced basal PA tone that is present in CH rats and relaxed PA rings precontracted with phenylephrine in both control and CH rats. These data show that sildenafil is a potent pulmonary artery relaxant in CH rats and that it normalizes CH-induced increases in resting [Ca2+]i and basal tone. Consequently, pharmacological inhibition of sildenafil-sensitive PDE5 downregulates the Ca2+ signaling pathway involved in this model of pulmonary hypertension.
authors.affiliation: Laboratoire de Physiologie Cellulaire Respiratoire, INSERM (E 356 and IFR 4 Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Pauvert
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
authors.forename: Eric
authors.initials: E
authors.lastname: Rousseau
authors.forename: Roger
authors.initials: R
authors.lastname: Marthan
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Savineau
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002908:Chronic Disease; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D000860:Hypoxia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011687:Purines; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D002110:Caffeine; D000068677:Sildenafil Citrate; D002118:Calcium