[E 4021, a cGMP phosphodiesterase inhibitor, is a selective pulmonary vasodilator in chronically hypoxic pulmonary hypertensive rats].
To test whether a potent cGMP-specific phosphodiesterase inhibitor, E 4021, is a selective pulmonary vasodilator in pulmonary hypertension, we studied its acute hemodynamic effects in conscious, chronically hypoxic pulmonary hypertensive rats. Chronically hypoxic pulmonary hypertension was induced by keeping adult Sprague-Dawley rats in a hypobaric chamber for 3 weeks. Two days after catheterization. E 4021 was injected intravenously at doses of 3, 10, 30, 100, 300, and 1,000 micrograms/kg at 10-min intervals. E 4021 caused significant decreases in mean pulmonary arterial pressure of 11 +/- 5, 12 +/- 6, and 18 +/- 5% at doses of 100, 300, and 1,000 micrograms/kg, respectively. In contrast to its depressor effect on mean pulmonary arterial pressure, E 4021 decreased mean systemic arterial pressure significantly (by 9 +/- 2%) at a dose of 1,000 micrograms/kg only. Heart rate and cardiac output were unchanged after the administration of E 4021. Tissue cGMP-specific phosphodiesterase activity was markedly higher in lung than in aorta. These results indicate that E 4021 is a relatively selective pulmonary vasodilator in chronically hypoxic pulmonary hypertensive rats. We conclude E 4021 may be useful for the treatment of pulmonary hypertension.
Yamaguchi
K
K
Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Oka
M
M
Nishino
M
M
Hanasato
N
N
Kira
S
S
Fukuchi
Y
Y
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia / Q000188:drug therapy*; D008168:Lung / Q000201:enzymology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000503:physiopathology; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000627:therapeutic use*
C091517:E 4021; D010726:Phosphodiesterase Inhibitors; D010880:Piperidines; D011799:Quinazolines; D014665:Vasodilator Agents; D015106:3',5'-Cyclic-GMP Phosphodiesterases