title: Relaxant effects of selective phosphodiesterase inhibitors on U46619 precontracted human intralobar pulmonary arteries and role of potassium channels.
abstract: We examined the influence of K+ channel antagonists on the vasorelaxation induced by theophylline (non selective PDEI), siguazodan (PDE3I), rolipram (PDE4I) and zaprinast (PDE5I) in human intralobar pulmonary arteries. All PDEI tested induced a concentration-dependent relaxation with theophylline being significantly (p < 0.05) more efficient and rolipram more potent than PDE5I and PDE3I (Emax values, expressed as a percentage of maximal relaxation by papaverine 10(-4)M, were 92% +/- 2%, 84% +/- 8%, 90% +/- 4% and 99% +/- 1%, and pD2 values were 7.30 +/- 0.35, 6.14 +/- 0.25, 5.86 +/- 0.17, and 4.85 +/- 0.47 for rolipram, siguazodan, zaprinast and theophylline, respectively). 4-Aminopyridine (4-AP, Kv, voltage dependent channel blocker, 1 mM) induced a significant increase (+17% p < 0.05) of U46619-induced vasoconstriction whereas the other K+-channels blockers, glibenclamide (KATP channels, 1 microM) charybdotoxin (predominant BKCa, large conductance Ca2+-sensitive K+ channels, 0.1 microM) and apamine (SKCa, small conductance, 0.3 microM) were without effect. The concentration response curves (CRC) for rolipram were significantly shifted to the right by glibenclamide (1 microM), charybdotoxin (0.1 microM) and 4-AP (1 mM). The CRC for siguazodan was significantly displaced to the right by 4-AP. None of the potassium channel blockers displaced the CRC for zaprinast and theophylline. Apamine was without effect on the CRC for all the PDEI used in this study. (1) PDE3, 4 and 5 are functionally present in human intralobar pulmonary arteries; (2) the vasoconstriction induced by U46619 is downregulated by 4-aminopyridine sensitive-K+ channels; (3) the relaxant effects of rolipram (PDE4I) are partly mediated through KATP, BKCa, and Kv potassium channels and those of siguazodan (PDE3I) by Kv potassium channels.
authors.affiliation: Laboratory of Cardiovascular Physiopathology and Pharmacology, Faculty of Medicine, Jeanne d'Arc, Dijon, France. Marc.Bardou@u-bourgogne.fr
authors.forename: Marc
authors.initials: M
authors.lastname: Bardou
authors.forename: Françoise
authors.initials: F
authors.lastname: Goirand
authors.forename: Alain
authors.initials: A
authors.lastname: Bernard
authors.forename: Pascal
authors.initials: P
authors.lastname: Guerard
authors.forename: Mylene
authors.initials: M
authors.lastname: Gatinet
authors.forename: Philippe
authors.initials: P
authors.lastname: Devillier
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Dumas
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Morcillo
authors.forename: Luc
authors.initials: L
authors.lastname: Rochette
authors.forename: Monique
authors.initials: M
authors.lastname: Dumas
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000368:Aged; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D010726:Phosphodiesterase Inhibitors; D015221:Potassium Channels; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid