E4021, a selective phosphodiesterase 5 inhibitor, potentiates the vasodilator effect of inhaled nitric oxide in isolated perfused rat lungs.
To test whether E4021, a potent selective cyclic guanosine 3'-5'-monophosphate (cGMP) phosphodiesterase inhibitor, causes pulmonary vasodilation and whether it enhances the vasodilator action of inhaled nitric oxide (NO), we studied its effects on pulmonary vascular tone and inhaled NO-induced pulmonary vasodilation in isolated perfused rat lungs. Lungs were perfused at a constant flow rate with salt-Ficoll solution and ventilated with air plus 5% CO2. After equilibration, vasodilator responses to either E4021, inhaled NO, or both were evaluated under conditions of increased perfusion pressure induced by infusion of U46619. E4021 had no effect on the baseline perfusion pressure, whereas it caused dose-dependent pulmonary vasodilation when the vasomotor tone was increased by U46619. Inhaled 1, 5, and 20 ppm NO reduced the increased perfusion pressure by 60+/-5%, 83+/-3%, and 92+/-2%, respectively. Pretreatment with E4021 significantly potentiated the vasodilator effect of 1 ppm NO (from 53+/-6% to 71+/-2%; p < 0.05) but did not alter that of 5 ppm NO (from 77+/-3% to 78+/-4%; p > 0.05). In addition, pretreatment with E4021 significantly augmented the vasodilator response to sodium nitroprusside but not to isoproterenol. These results indicate that E4021 causes pulmonary vasodilation and potentiates the vasodilator effect of low concentrations of inhaled NO, probably through a cGMP-dependent mechanism in salt-solution perfused rat lungs. We conclude that E4021 may possibly be useful for the treatment of pulmonary hypertension, either alone or in combination with inhaled NO.
Ohnishi
M
M
Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Oka
M
M
Muramatsu
M
M
Sato
K
K
Kira
S
S
Fukuchi
Y
Y
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000280:Administration, Inhalation; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004357:Drug Synergism; D006976:Hypertension, Pulmonary / Q000503:physiopathology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010477:Perfusion; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D001993:Bronchodilator Agents; C091517:E 4021; D010726:Phosphodiesterase Inhibitors; D010880:Piperidines; D011799:Quinazolines; D009599:Nitroprusside; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP; D007545:Isoproterenol