Cardiac ion channel current modulation by the CFTR inhibitor GlyH-101

Biochem Biophys Res Commun. 2011 Apr 29;408(1):12-7. doi: 10.1016/j.bbrc.2011.03.089. Epub 2011 Mar 31.


The role in the heart of the cardiac isoform of the cystic fibrosis transmembrane conductance regulator (CFTR), which underlies a protein kinase A-dependent Cl(-) current (I(Cl.PKA)) in cardiomyocytes, remains unclear. The identification of a CFTR-selective inhibitor would provide an important tool for the investigation of the contribution of CFTR to cardiac electrophysiology. GlyH-101 is a glycine hydrazide that has recently been shown to block CFTR channels but its effects on cardiomyocytes are unknown. Here the action of GlyH-101 on cardiac I(Cl.PKA) and on other ion currents has been established. Whole-cell patch-clamp recordings were made from rabbit isolated ventricular myocytes. GlyH-101 blocked I(Cl.PKA) in a concentration- and voltage-dependent fashion (IC(50) at +100 mV=0.3 ± 1.5 μM and at -100 mV=5.1 ± 1.3 μM). Woodhull analysis suggested that GlyH-101 blocks the open pore of cardiac CFTR channels at an electrical distance of 0.15 ± 0.03 from the external membrane surface. A concentration of GlyH-101 maximally effective against I(Cl.PKA) (30 μM) was tested on other cardiac ion currents. Inward current at -120 mV, comprised predominantly of the inward-rectifier background K(+) current, I(K1), was reduced by ∼43% (n=5). Under selective recording conditions, the Na(+) current (I(Na)) was markedly inhibited by GlyH-101 over the entire voltage range (with a fractional block at -40 mV of ∼82%; n=8). GlyH-101 also produced a voltage-dependent inhibition of L-type Ca(2+) channel current (I(Ca,L)); fractional block at +10 mV of ∼49% and of ∼28% at -10 mV; n=11, with a ∼-3 mV shift in the voltage-dependence of I(Ca,L) activation. Thus, this study demonstrates for the first time that GlyH-101 blocks cardiac I(Cl.PKA) channels in a similar fashion to that reported for recombinant CFTR. However, inhibition of other cardiac conductances may limit its use as a CFTR-selective blocker in the heart.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, L-Type / physiology
  • Cells, Cultured
  • Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors*
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Heart / drug effects*
  • Heart / physiology
  • Hydrazines / pharmacology*
  • Male
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology
  • Potassium Channels, Inwardly Rectifying / antagonists & inhibitors
  • Potassium Channels, Inwardly Rectifying / physiology
  • Rabbits
  • Sodium Channels / physiology


  • Calcium Channels, L-Type
  • Hydrazines
  • N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide
  • Potassium Channels, Inwardly Rectifying
  • Sodium Channels
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Glycine