Effects of phosphodiesterase inhibitors on hypoxic pulmonary vasoconstriction. Influence of K(+) channels and nitric oxide.
We studied the relaxant effects of the cyclic nucleotide phosphodiesterase inhibitors theophylline (non-selective), rolipram (type IV, 3',5'-cyclic monophosphate (cAMP)-specific) and zaprinast (type V, 3',5'-cyclic monophosphate (cGMP)-specific) on the hypoxic vasoconstriction in the isolated perfused rat lung and the involvement of K(+) channels and nitric oxide (NO) in these effects. K(+) channels were inhibited by glibenclamide, charybdotoxin, apamin and 4-aminopyridine and nitric oxide synthase by L-N(G)-nitroarginine methyl ester (L-NAME). Hypoxic ventilation produced a significant pressure response. L-NAME and 4-aminopyridine increased this response. Rolipram, zaprinast and theophylline shared the ability to oppose the hypoxic pulmonary vasoconstriction. The order of potency was zaprinast>rolipram>theophylline. Glibenclamide partially inhibited the relaxant effects of rolipram and theophylline. Charybdotoxin inhibited the dilator response to rolipram. Apamin inhibited partially the vasodilation induced by rolipram and zaprinast. 4-Aminopyridine inhibited partially the relaxant effects of theophylline. L-NAME failed to block the effects of the three compounds. These data illustrate different pharmacological profiles according to the phosphodiesterase inhibitors and support the potential interest of selective inhibitors as relaxant agents in pulmonary vessels.
Goirand
F
F
Laboratoire de Physiopathologie et de Pharmacologie Cardiovasculaires Expérimentales, Faculté de Médecine, 7 Bd Jeanne d'Arc, BP 87900, 21079 cedex, Dijon, France. Françoise.Goirand@u-bourgogne.fr
Bardou
M
M
Dumas
J
J
Rochette
L
L
Dumas
M
M
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011688:Purinones; D018999:Charybdotoxin; D001030:Apamin; D009569:Nitric Oxide; D015761:4-Aminopyridine; D013806:Theophylline; D019001:Nitric Oxide Synthase; C011145:zaprinast; D020889:Rolipram; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester