A mechanism for the potential proarrhythmic effect of acidosis, bradycardia, and hypokalemia on the blockade of human ether-a-go-go-related gene (HERG) channels.
Many drugs are proarrhythmic by inhibiting the cardiac rapid delayed rectifier potassium channel (IKr). In this study, we use quinidine as an example of highly proarrhythmic agent to investigate the risk factors that may facilitate the proarrhythmic effects of drugs. We studied the influence of pacing, extracellular potassium, and pH on quinidine's IKr blocking effect, all potential factors influencing quinidine's cardiac toxicity. Since the HERG gene encodes IKr, we studied quinidine's effect on HERG expressed in Xenopus oocytes by the 2-electrode voltage clamp technique. When extracellular K+ was 5 mmol/L, quinidine blocked the HERG current dose dependently, with an IC50 of 6.3 +/- 0.2 micromol/L. The blockade was much more prominent at more positive membrane potentials. The inhibition of HERG by quinidine was not use dependent. There was no significant difference between block with or without pacing. When extracellular K+ was lowered to 2.5 mmol/L, the current inhibition by quinidine was enhanced, and IC50 decreased to 4.6 +/- 0.5 micromol/L. At 10 mmol/L extracellular K+, there was less inhibition by quinidine and the IC50 was 11.2 +/- 3.1 micromol/L. Extracellular acidification decreased both steady state and tail currents of HERG. We conclude that the inhibitory effect of quinidine on IKr was decreased with extracellular acidification, which may produce heterogeneity in the repolarization between normal and ischemic cardiac tissue. Thus, the use-independent blockade of IKr by QT-prolonging agents such as quinidine may contribute to cardiac toxicity with bradycardia, hypokalemia, and acidosis further exaggerating the proarrhythmic potential of these agents.
Lin
Congrong
C
Department of Pharmacology, Rush University, Chicago, Illinois 60612, USA.
Cvetanovic
Ivana
I
Ke
Xiaogang
X
Ranade
Vasant
V
Somberg
John
J
D000138:Acidosis / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism*; D001919:Bradycardia / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007008:Hypokalemia / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D011802:Quinidine / Q000009:adverse effects; D014982:Xenopus laevis
D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011802:Quinidine; D011188:Potassium