A SELECTIVE TYPE-V PHOSPHODIESTERASE INHIBITOR, E4021, DILATES PORCINE LARGE CORONARY-ARTERY

We investigated the inhibitory effects of a newly synthesized compound , sodium yl)-aminoquinazolin-2--yl]piperidine-4-carboxylate sesquihydr ate (E4021), on five phosphodiesterase (PDE) isozymes isolated from po rcine aortic smooth muscle. E4021 specifically inhibited type V phosph odiesterase (cyclic guanosine monophosphate [cGMP]-specific PDE) in a competitive manner. A comparison of the inhibitory profiles of zaprina st and E4021 indicated that E4021 is 100 times more potent and selecti ve as a type V PDE inhibitor. E4021 caused a significant and sustained increase in the cGMP level in endothelium-denuded porcine coronary ar tery, but it had no effect on the cAMP level. This compound had a rela xant effect in porcine coronary artery precontracted by prostaglandin F-2 alpha in the absence of endothelial cells and relaxed it more mark edly in the presence of endothelial cells. E4021 had a synergistic eff ect with nitroglycerin in both the increase in cGMP level and the rela xant effect in isolated porcine coronary artery. E4021 caused a dose-d ependent dilation of the large epicardial coronary artery, with a redu ction in mean pulmonary arterial pressure, in conscious pigs instrumen ted chronically with a pair of piezoelectric crystals. These results s uggest that the highly selective and potent inhibitor of type V phosph odiesterase E4021 causes relaxation of the large coronary artery via a n increase in the cGMP level.