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

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 (ICl.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 ICl.PKA and on other ion currents has been established. Whole-cell patch-clamp recordings were made from rabbit isolated ventricular myocytes. GlyH-101 blocked ICl.PKA in a concentration- and voltage-dependent fashion (IC50 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 ICl.PKA (30 μM) was tested on other cardiac ion currents. Inward current at −120 mV, comprised predominantly of the inward-rectifier background K+ current, IK1, was reduced by ∼43% (n = 5). Under selective recording conditions, the Na+ current (INa) 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 Ca2+ channel current (ICa,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 ICa,L activation. Thus, this study demonstrates for the first time that GlyH-101 blocks cardiac ICl.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.

► We report effects of the glycine hydrazide CFTR inhibitor GlyH-101 on cardiac ion channels.
► GlyH-101 inhibits cardiac CFTR in a concentration and voltage-dependent manner.
► GlyH-101 binds within the pore towards the external surface of open cardiac CFTR channels.
► Inhibitory effects on cardiac Na and Ca channels may limit its value as a selective CFTR blocker.