alexa BeKm-1, a peptide inhibitor of human ether-a-go-go-related gene potassium currents, prolongs QTc intervals in isolated rabbit heart.
Clinical Sciences

Clinical Sciences

Cardiovascular Pharmacology: Open Access

Author(s): Qu Y, Fang M, Gao B, Chui RW, Vargas HM, Qu Y, Fang M, Gao B, Chui RW, Vargas HM

Abstract Share this page

Abstract Drug-induced cardiac arrhythmia, specifically Torsades de pointes, is associated with QT/QTc interval prolongation, thus prolongation of the QT interval is considered as a biomarker for Torsades de pointes risk (N Engl J Med 350:1013-1022, 2004). Specific inhibition of human ether-a-go-go-related gene (hERG) potassium channels has been recognized as the main mechanism for QT prolongation (Cardiovasc Res 58:32-45, 2003). This mechanism has been demonstrated for a variety of small-molecule agents, which access the inner pore of the hERG channel preferentially from inside the cell. Peptide inhibitors of hERG, such as BeKm-1, interact with the extracellular amino acid residues close to the external pore region of the channel. In this study, the isolated rabbit heart was used to assess whether BeKm-1 could induce QTc prolongation like dofetilide and N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide (E-4031). Five hearts were perfused with 10 and 100 nM BeKm-1 sequentially. ECG parameters and left ventricular contractility were measured with spontaneously beating hearts. Both concentrations of BeKm-1 prolonged QTc intervals significantly and concentration-dependently (4.7 and 16.3\% at 10 and 100 nM, respectively). When evaluated for their inhibitory effect in a hERG functional assay, BeKm-1, dofetilide, and E-4031 caused QTc prolongation at concentrations that caused significant hERG channel inhibition. Lastly, two polyclonal anti-hERG antibodies were also assessed in the hERG channel assay and found to be devoid of any inhibitory effect. These results indicated that the isolated rabbit heart assay can be used to measure QTc changes caused by specific hERG inhibition by peptides that specifically block the external pore region of the channel. This article was published in J Pharmacol Exp Ther and referenced in Cardiovascular Pharmacology: Open Access

Relevant Expert PPTs

Relevant Speaker PPTs

  • Donald silverberg
    Is correction of iron deficiency a new addition to the treatment of heart failure?
    PPT Version | PDF Version
  • Ahmed Zeidan
    Effects of intravenous iron in chronic kidney disease and heart failure
    PPT Version | PDF Version
  • Rohit A
    Cardiovascular risk prediction using WHO/ISH chart in urban and rural subjects attending diabetes screening clinic: A pilot study
    PPT Version | PDF Version
  • Yosef Yarden
    Classically, the 3’untranslated region (3’UTR) is that region in eukaryotic protein-coding genes from the translation termination codon to the polyA signal. It is transcribed as an integral part of the mRNA encoded by the gene. However, there exists another kind of RNA, which consists of the 3’UTR alone, without all other elements in mRNA such as 5’UTR and coding region. The importance of independent 3’UTR RNA (referred as I3’UTR) was prompted by results of artificially introducing such RNA species into malignant mammalian cells. Since 1991, we found that the middle part of the 3’UTR of the human nuclear factor for interleukin-6 (NF-IL6) or C/EBP gene exerted tumor suppression effect in vivo. Our subsequent studies showed that transfection of C/EBP 3’UTR led to down-regulation of several genes favorable for malignancy and to up-regulation of some genes favorable for phenotypic reversion. Also, it was shown that the sequences near the termini of the C/EBP 3’UTR were important for its tumor suppression activity. Then, the C/EBP 3’UTR was found to directly inhibit the phosphorylation activity of protein kinase CPKC in SMMC-7721, a hepatocarcinoma cell line. Recently, an AU-rich region in the C/EBP 3’UTR was found also to be responsible for its tumor suppression. Recently we have also found evidence that the independent C/EBP 3’UTR RNA is actually exists in human tissues, such as fetal liver and heart, pregnant uterus, senescent fibroblasts etc. Through 1990’s to 2000’s, world scientists found several 3’UTR RNAs that functioned as artificial independent RNAs in cancer cells and resulted in tumor suppression. Interestingly, majority of genes for these RNAs have promoter-like structures in their 3’UTR regions, although the existence of their transcribed products as independent 3’UTR RNAs is still to be confirmed. Our studies indicate that the independent 3’UTR RNA is a novel non-coding RNA species whose function should be the regulation not of the expression of their original mRNA, but of some essential life activities of the cell as a whole.
    PPT Version | PDF Version
  • Myriam Isnard-Rouchon
    Cardiovascular risk factors evolution during 6 months intra dialytic aerobic cycling program in hemodaylais patients: Hypertension, hyperlipidemia, hemoglobin stability and cardiovascular morbidity in hemodaylais patients
    PPT Version | PDF Version
  • Mauricio Laerte Silva
    Cardiac Diastolic Function in Pediatric AIDS/HIV-carriers: Assessment, Treatment and Prevention of Future Cardiovascular Diseases
    PPT Version | PDF Version
  • Tayfun Uzbay
    Alzheimer disease and neuroplasticity: New approaches and new targets in pharmacotherapy
    PPT Version | PDF Version
  • Ishfaq A Bukhari
    Protective Effect of Diltiazem and Fenofibrate Against Ischemia-reperfusion Induced Cardiac Arrhythmias in the Isolated Rat Heart.
    PPT Version | PDF Version
  • Vladimir E. Bondarenko
    Mathematical model of β1-adrenergic signaling in mouse ventricular myocytes as an in silico tool for the cardiovascular drug test
    PPT Version | PDF Version
  • A Martin Gerdes
    Wrong about β-blockers! Wrong about positive inotropes! Wrong about Thyroid Hormone treatment of Heart Failure?
    PDF Version
  • Fatih Yalcin
    PDF Version
  • Pollen K F Yeung
    ATP Metabolism as Biomarker Target for Cardiovascular Protection and Toxicity
    PDF Version
  • Samuel C Dudley
    Novel biomarkers for diastolic heart failure
    PDF Version
  • Abdulaziz U Joury
    Acute Myocardial Infarction as First Presentation among patients with Coronary Heart Disease
    PPT Version | PDF Version
  • Maravic Stojkovic V
    Blood Loss and Intraoperative Salvage Procedure in Patients Underwent Re-operation Coronary Artery Bypass
    PDF Version

Recommended Conferences

Peer Reviewed Journals
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version