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.