Referenced in: none

Automatically associated channels: Kv11.1

Title: Cardiovascular assessment of ER-118585, a selective phosphodiesterase 5 inhibitor.

Authors: Hiroshi Mizuno, Hideyuki Adachi, Junko Kimura, Yoshio Sawa, Motoharu Kakiki, Kate Lansdell, Mamoru Saito, William David Kerns

Journal, date & volume: Biol. Pharm. Bull., 2003 Dec , 26, 1661-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/14646167

Abstract
The aim of this study was to assess the cardiovascular effects of a selective phosphodiesterase 5 inhibitor ER-118585, 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinecarbonitrile monohydrochloride. The present results indicated that 1) ER-118585 significantly inhibited the human ether-a-go-go related gene (HERG) tail current at 10 nM and above with an IC(50) value of 40.7 nM in human embryonic kidney 293 cells transfected with HERG cDNA; 2) ER-118585 at 100 and 1000 nM significantly increased the action potential duration (APD) at 50% and 90% repolarization in isolated papillary muscles of guinea pig; and 3) intravenous infusion of ER-118585 at 10 microg/kg/min significantly prolonged the QT interval by 10.5+/-1.6% from 281+/-2 ms to 311+/-6 ms in six anesthetized dogs subjected to atrial pacing. In consideration of both the plasma concentration of ER-118585 (984+/-78 nM, n=3) and its protein binding fraction (99.0+/-0.1%, n=5), the free plasma concentration was estimated at 9.8+/-0.8 nM, which is consistent with the minimum concentration of HERG current inhibition. In conclusion, these evaluation methods demonstrated that ER-118585 could prolong the QT interval via APD prolongation, attributable to the inhibition of the HERG potassium current.