A selective type V phosphodiesterase inhibitor, E4021, dilates porcine large coronary artery.
We investigated the inhibitory effects of a newly synthesized compound, sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2-y l]piperidine-4- carboxylate sesquihydrate (E4021), on five phosphodiesterase (PDE) isozymes isolated from porcine aortic smooth muscle. E4021 specifically inhibited type V phosphodiesterase (cyclic guanosine monophosphate [cGMP]-specific PDE) in a competitive manner. A comparison of the inhibitory profiles of zaprinast and E4021 indicated that E4021 is 100 times more potent and selective as a type V PDE inhibitor. E4021 caused a significant and sustained increase in the cGMP level in endothelium-denuded porcine coronary artery, but it had no effect on the cAMP level. This compound had a relaxant effect in porcine coronary artery precontracted by prostaglandin F2 alpha in the absence of endothelial cells and relaxed it more markedly in the presence of endothelial cells. E4021 had a synergistic effect with nitroglycerin in both the increase in cGMP level and the relaxant effect in isolated porcine coronary artery. E4021 caused a dose-dependent dilation of the large epicardial coronary artery, with a reduction in mean pulmonary arterial pressure, in conscious pigs instrumented chronically with a pair of piezoelectric crystals. These results suggest that the highly selective and potent inhibitor of type V phosphodiesterase E4021 causes relaxation of the large coronary artery via an increase in the cGMP level.
Saeki
T
T
Department of Cardiovascular Disease Research, Eisai Tsukuba Research Laboratories, Ibaraki, Japan.
Adachi
H
H
Takase
Y
Y
Yoshitake
S
S
Souda
S
S
Saito
I
I
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011817:Rabbits; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
C091517:E 4021; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010880:Piperidines; D011799:Quinazolines; D006152:Cyclic GMP; D007548:Isosorbide Dinitrate