Absence of clinically important HERG channel blockade by three compounds that inhibit phosphodiesterase 5--sildenafil, tadalafil, and vardenafil
Abstract
Compounds that inhibit phosphodiesterase 5 (PDE5) have been developed for the treatment of erectile dysfunction. Because men with erectile dysfunction frequently have comorbid cardiovascular disease, they may have limited cardiac repolarization reserve and be at risk of arrhythmia if treated with medications that prolong ventricular repolarization. The human ether-a-go-go related gene (HERG) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the ability of three compounds that inhibit PDE5--sildenafil, tadalafil, and vardenafil--to block the HERG channel. Using a whole cell variant of the patch-clamp method, the HERG current was measured in a stably transfected human embryonic kidney cell line expressing the HERG channel. The compounds produced dose-dependent reductions in HERG current amplitude over a concentration range of 0.1 to 100 microM. The IC50 values were 12.8 microM for vardenafil and 33.3 microM for sildenafil. Because the maximum soluble concentration of tadalafil (100 microM) produced only a 50.9% inhibition of the HERG current amplitude, the IC50 value for tadalafil could not be determined with the Hill equation. Tadalafil had the weakest capacity to block the HERG channel, producing a 50.9% blockade at the maximum soluble concentration (100 microM), compared with 86.2% for vardenafil (100 microM) and 75.2% for sildenafil (100 microM). In conclusion, the concentrations of the…
Read the paper
Related studies
- Drug repositioning: a brief overview
- Cyclic nucleotide phosphodiesterases in Drosophila melanogaster
- Time-resolved in silico modeling of fine-tuned cAMP signaling in platelets: feedback loops, titrated phosphorylations and pharmacological modulation
- Current View on Green Tea Catechins Formulations, Their Interactions with Selected Drugs, and Prospective Applications for Various Health Conditions
- In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease
- Development and In Vitro Evaluation of Controlled Release Viagra® Containing Poloxamer-188 Using Gastroplus™ PBPK Modeling Software for In Vivo Predictions and Pharmacokinetic Assessments
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.