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Cardiovascular Assessment of ER-118585, a Selective Phosphodiesterase 5 Inhibitor

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

Biological and Pharmaceutical Bulletin, 2003, Vol.26(12), pp.1661-1667 [Periódico revisado por pares]

Tokyo: The Pharmaceutical Society of Japan

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Título:
Cardiovascular Assessment of ER-118585, a Selective Phosphodiesterase 5 Inhibitor
Autor: Mizuno, Hiroshi ; Adachi, Hideyuki ; Kimura, Junko ; Sawa, Yoshio ; Kakiki, Motoharu ; Lansdell, Kate ; Saito, Mamoru ; Kerns, William David
Assuntos: 3',5'-Cyclic-GMP Phosphodiesterases ; action potential duration ; Action Potentials - drug effects ; Action Potentials - physiology ; Animals ; Biological and medical sciences ; Cardiac Pacing, Artificial ; Cardiovascular Diseases - drug therapy ; Cardiovascular system ; Cell Line ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Dogs ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Electrocardiography ; Electrophysiology ; Guinea Pigs ; human ether-a-go-go related gene ; Humans ; Infusions, Intravenous ; Kidney - cytology ; Long QT Syndrome - chemically induced ; Long QT Syndrome - genetics ; Long QT Syndrome - prevention & control ; Male ; Medical sciences ; Miscellaneous ; Papillary Muscles - drug effects ; Papillary Muscles - physiology ; Patch-Clamp Techniques ; Pharmacology. Drug treatments ; Phosphodiesterase Inhibitors - adverse effects ; Phosphodiesterase Inhibitors - blood ; Phosphodiesterase Inhibitors - pharmacology ; Phosphoric Diester Hydrolases - drug effects ; Phosphoric Diester Hydrolases - metabolism ; Phthalazines - pharmacology ; Piperidines - pharmacology ; Potassium Channels, Voltage-Gated - antagonists & inhibitors ; Potassium Channels, Voltage-Gated - drug effects ; Potassium Channels, Voltage-Gated - genetics ; Protein Binding ; Pyridines - pharmacology ; QT prolongation ; Spiro Compounds - pharmacology ; Transfection - methods ; Ventricular Function - drug effects ; Ventricular Function - genetics ; Ventricular Function - physiology ; Ventricular Premature Complexes - drug therapy ; Ventricular Premature Complexes - genetics ; Ventricular Premature Complexes - prevention & control
É parte de: Biological and Pharmaceutical Bulletin, 2003, Vol.26(12), pp.1661-1667
Descrição: 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 IC50 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 μg/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.
Editor: Tokyo: The Pharmaceutical Society of Japan
Idioma: Inglês;Japonês

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Cardiovascular Assessment of ER-118585, a Selective Phosphodiesterase 5 Inhibitor

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

Tokyo: The Pharmaceutical Society of Japan

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